Hot off the presses! Jul 22 Immunity

The Jul 22 issue of the Immunity is now up on Pubget (About Immunity): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• T Cell Receptor Structures: Three for the Price of One
  - Immunity 35(1):1-3 (2011)
  A T cell receptor (TCR) that binds both major histocompatibility complex (MHC) class I and class II molecules reveals a novel structural variation that can potentially allow a single TCR to have three widely differing binding sites (Yin et al., 2011).
• Love Triangle between Unc93B1, TLR7, and TLR9 Prevents Fatal Attraction
  - Immunity 35(1):3-5 (2011)
  Unc93B1, a multitransmembrane ER-resident protein, controls intracellular trafficking of endosomal Toll-like receptors. In this issue of Immunity, Fukui et al. (2011) revealed that Unc93B1 regulates differential transport of TLR7 and TLR9 into signaling endosomes to prevent autoimmunity.
• It Takes Two to Tango
  - Immunity 35(1):6-8 (2011)
  Regulatory T (Treg) cells are essential for maintaining immune tolerance. In this issue of Immunity, Haribhai et al. (2011) demonstrate that both subsets of Treg cells, natural and induced, are necessary to achieve tolerance, probably because of their nonoverlapping T cell receptor repertoires.
• Sensing Retroviruses
  - Immunity 35(1):8-10 (2011)
  Sensing pathogens is an essential first step in the initiation of a host response to infection. In this issue of Immunity, Kane et al. (2011) used mouse models to demonstrate that Toll-like receptor 7 is required for the generation of an antibody response to infection by retroviruses.
• Beating Atomic Swords into Immunological Ploughshares
  - Immunity 35(1):10-12 (2011)
  Deliberate redirection of T cell responses to human immunodeficiency virus-1 might enhance immunity and thus aid viral containment. Dahirel et al. (2011) identify candidate antigens to achieve this with a theory derived from physics.
• The Role of Retinoic Acid in Tolerance and Immunity
  - Immunity 35(1):13-22 (2011)
  Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology.
• A Single T Cell Receptor Bound to Major Histocompatibility Complex Class I and Class II Glycoproteins Reveals Switchable TCR Conformers
  - Immunity 35(1):23-33 (2011)
  Major histocompatibility complex class I (MHCI) and MHCII proteins differ in structure and sequence. To understand how T cell receptors (TCRs) can use the same set of variable regions to bind both proteins, we have presented a comparison of a single TCR bound to both MHCI and MHCII ligands. The TCR adopts similar orientations on both ligands with TCR amino acids thought to be evolutionarily conserved for MHC interaction occupying similar positions on the MHCI and MHCII helices. However, the TCR antigen-binding loops use different conformations when interacting with each ligand. Most importantly, we observed alternate TCR core conformations. When bound to MHCI, but not MHCII, Vα disengages from the Jα β strand, switching Vα's position relative to Vβ. In several other structures, either Vα or Vβ undergoes this same modification. Thus, both TCR V-domains can switch among alternate conformations, perhaps extending their ability to react with different MHC-peptide li! gands.
• Anthrax Toxin Induces Macrophage Death by p38 MAPK Inhibition but Leads to Inflammasome Activation via ATP Leakage
  - Immunity 35(1):34-44 (2011)
  Detection of microbial constituents by membrane associated and cytoplasmic pattern recognition receptors is the essence of innate immunity, leading to activation of protective host responses. However, it is still unclear how immune cells specifically respond to pathogenic bacteria. Using virulent and nonvirulent strains of Bacillus anthracis, we have shown that secretion of ATP by infected macrophages and the sequential activation of the P2X7 purinergic receptor and nucleotide binding oligomerization domain (NOD)-like receptors are critical for IL-1-dependent host protection from virulent B. anthracis. Importantly, lethal toxin produced by virulent B. anthracis blocked activation of protein kinases, p38 MAPK and AKT, resulting in opening of a connexin ATP release channel and induction of macrophage death. Prevention of cell death or ATP release through constitutive p38 or AKT activation interfered with inflammasome activation and IL-1β production, thereby compromising! antimicrobial immunity.
• Signaling by the Phosphatase MKP-1 in Dendritic Cells Imprints Distinct Effector and Regulatory T Cell Fates
  - Immunity 35(1):45-58 (2011)
  Naive T cells respond to antigens by differentiating into effector and regulatory lineages. Whereas the roles of T cell-intrinsic pathways have been extensively studied, how T cell lineage choices are controlled by innate immune signals remains elusive. Here we report that dendritic cell (DC)-expressed phosphatase MKP-1, a negative regulator of the MAP kinases, programmed reciprocal T helper 1 (Th1) and Th17 cell differentiation by modulating IL-12-STAT4 and IL-6-STAT3 axes and cytokine receptor expression at the DC-T cell interface. MKP-1 was regulated by innate recognition signals and its deficiency disrupted antimicrobial responses and promoted T cell-mediated inflammation. Moreover, MKP-1 inhibited induction of regulatory T cells by downregulating TGF-β2 production from DCs. Our findings identify a regulatory circuit linking MKP-1 signaling in DCs, production of polarizing cytokines, and integration of DC-derived signals in responding T cells, that bridges innate ! and adaptive immunity to coordinate protective immunity and immunopathology.
• Skint-1 Identifies a Common Molecular Mechanism for the Development of Interferon-γ-Secreting versus Interleukin-17-Secreting γδ T Cells
  - Immunity 35(1):59-68 (2011)
  Murine T cell development begins with the generation of a unique Vγ5+Vδ1+ epidermal γδ T cell compartment and a unique, more broadly distributed Vγ6+Vδ1+ subset that is an important source of interleukin-17 (IL-17). This study showed that these respective functional programs were determined by Skint-1, a thymic epithelial cell determinant. By engaging Skint-1+ cells, Vγ5+Vδ1+ thymocytes induced an Egr3-mediated pathway, provoking differentiation and the potential to produce IFN-γ while suppressing the γδ T cell lineage factor, Sox13, and a RORγt transcription factor-associated IL-17-producing capacity. Hence, the functions of the earliest T cells are substantially preprogrammed in the thymus. Additionally, the phenotype of Skint-1-selected fetal thymocytes permitted identification in the adult thymus of an analogous gene regulatory network regulated by the γδ T cell receptor. Hence, these observations describe a molecular pathway by which distinct stress-! responsive lymphocyte repertoires may emerge throughout ontogeny and offer parallels with emerging perspectives on the functional selection of other lymphoid cells.
• Unc93B1 Restricts Systemic Lethal Inflammation by Orchestrating Toll-like Receptor 7 and 9 Trafficking
  - Immunity 35(1):69-81 (2011)
  Toll-like receptor-7 (TLR7) and 9, innate immune sensors for microbial RNA or DNA, have been implicated in autoimmunity. Upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, Unc93B1. Little is known, however, about a role for sensor transportation in controlling autoimmunity. TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7. TLR9 skewing is actively maintained by Unc93B1 and reversed to TLR7 if Unc93B1 loses preferential binding via a D34A mutation. We here demonstrate that mice harboring a D34A mutation showed TLR7-dependent, systemic lethal inflammation. CD4+ T cells showed marked differentiation toward T helper 1 (Th1) or Th17 cell subsets. B cell depletion abolished T cell differentiation and systemic inflammation. Thus, Unc93B1 controls homeostatic TLR7 activation by balancing TLR9 to TLR7 trafficking.
• The Ubiquitin-Editing Protein A20 Prevents Dendritic Cell Activation, Recognition of Apoptotic Cells, and Systemic Autoimmunity
  - Immunity 35(1):82-96 (2011)
  Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonical NF-κB activation. Tnfaip3fl/flCd11c-cre+ mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly—features of systemic lupus erythematosus—and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorp! hisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.
• The Costimulatory Molecule CD27 Maintains Clonally Diverse CD8+ T Cell Responses of Low Antigen Affinity to Protect against Viral Variants
  - Immunity 35(1):97-108 (2011)
  CD70 and CD27 are costimulatory molecules that provide essential signals for the expansion and differentiation of CD8+ T cells. Here, we show that CD27-driven costimulation lowered the threshold of T cell receptor activation on CD8+ T cells and enabled responses against low-affinity antigens. Using influenza infection to study in vivo consequences, we found that CD27-driven costimulation promoted a CD8+ T cell response of overall low affinity. These qualitative effects of CD27 on T cell responses were maintained into the memory phase. On a clonal level, CD27-driven costimulation established a higher degree of variety in memory CD8+ T cells. The benefit became apparent when mice were reinfected, given that CD27 improved CD8+ T cell responses against reinfection with viral variants, but not with identical virus. We propose that CD27-driven costimulation is a strategy to generate memory clones that have potential reactivity to a wide array of mutable pathogens.
• A Requisite Role for Induced Regulatory T Cells in Tolerance Based on Expanding Antigen Receptor Diversity
  - Immunity 35(1):109-122 (2011)
  Although both natural and induced regulatory T (nTreg and iTreg) cells can enforce tolerance, the mechanisms underlying their synergistic actions have not been established. We examined the functions of nTreg and iTreg cells by adoptive transfer immunotherapy of newborn Foxp3-deficient mice. As monotherapy, only nTreg cells prevented disease lethality, but did not suppress chronic inflammation and autoimmunity. Provision of Foxp3-sufficient conventional T cells with nTreg cells reconstituted the iTreg pool and established tolerance. In turn, acute depletion of iTreg cells in rescued mice resulted in weight loss and inflammation. Whereas the transcriptional signatures of nTreg and in vivo-derived iTreg cells were closely matched, there was minimal overlap in their T cell receptor (TCR) repertoires. Thus, iTreg cells are an essential nonredundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses.
• T Cell Surveillance of Oncogene-Induced Prostate Cancer Is Impeded by T Cell-Derived TGF-β1 Cytokine
  - Immunity 35(1):123-134 (2011)
  Tolerance induction in T cells takes place in most tumors and is thought to account for tumor evasion from immune eradication. Production of the cytokine TGF-β is implicated in immunosuppression, but the cellular mechanism by which TGF-β induces T cell dysfunction remains unclear. With a transgenic model of prostate cancer, we showed that tumor development was not suppressed by the adaptive immune system, which was associated with heightened TGF-β signaling in T cells from the tumor-draining lymph nodes. Blockade of TGF-β signaling in T cells enhanced tumor antigen-specific T cell responses and inhibited tumor development. Surprisingly, T cell- but not Treg cell-specific ablation of TGF-β1 was sufficient to augment T cell cytotoxic activity and blocked tumor growth and metastases. These findings reveal that T cell production of TGF-β1 is an essential requirement for tumors to evade immunosurveillance independent of TGF-β produced by tumors.
• Innate Immune Sensing of Retroviral Infection via Toll-like Receptor 7 Occurs upon Viral Entry
  - Immunity 35(1):135-145 (2011)
  Innate immune sensors are required for induction of pathogen-specific immune responses. Retroviruses are notorious for their ability to evade immune defenses and establish long-term persistence in susceptible hosts. However, some infected animals are able to develop efficient virus-specific immune responses, and thus can be employed for identification of critical innate virus-sensing mechanisms. With mice from two inbred strains that control retroviruses via adaptive immune mechanisms, we found that of all steps in viral replication, the ability to enter the host cell was sufficient to induce antivirus humoral immune responses. Virus sensing occurred in endosomes via a MyD88-Toll-like receptor 7-dependent mechanism and stimulated virus-neutralizing immunity independently of type I interferons. Thus, efficient adaptive immunity to retroviruses is induced in vivo by innate sensing of the early stages of retroviral infection.
• The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock
  - Immunity 35(1):146 (2011)
  

Hot off the presses! Jul 22 Immunity

The Jul 22 issue of the Immunity is now up on Pubget (About Immunity): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• T Cell Receptor Structures: Three for the Price of One
  - Immunity 35(1):1-3 (2011)
  A T cell receptor (TCR) that binds both major histocompatibility complex (MHC) class I and class II molecules reveals a novel structural variation that can potentially allow a single TCR to have three widely differing binding sites (Yin et al., 2011).
• Love Triangle between Unc93B1, TLR7, and TLR9 Prevents Fatal Attraction
  - Immunity 35(1):3-5 (2011)
  Unc93B1, a multitransmembrane ER-resident protein, controls intracellular trafficking of endosomal Toll-like receptors. In this issue of Immunity, Fukui et al. (2011) revealed that Unc93B1 regulates differential transport of TLR7 and TLR9 into signaling endosomes to prevent autoimmunity.
• It Takes Two to Tango
  - Immunity 35(1):6-8 (2011)
  Regulatory T (Treg) cells are essential for maintaining immune tolerance. In this issue of Immunity, Haribhai et al. (2011) demonstrate that both subsets of Treg cells, natural and induced, are necessary to achieve tolerance, probably because of their nonoverlapping T cell receptor repertoires.
• Sensing Retroviruses
  - Immunity 35(1):8-10 (2011)
  Sensing pathogens is an essential first step in the initiation of a host response to infection. In this issue of Immunity, Kane et al. (2011) used mouse models to demonstrate that Toll-like receptor 7 is required for the generation of an antibody response to infection by retroviruses.
• Beating Atomic Swords into Immunological Ploughshares
  - Immunity 35(1):10-12 (2011)
  Deliberate redirection of T cell responses to human immunodeficiency virus-1 might enhance immunity and thus aid viral containment. Dahirel et al. (2011) identify candidate antigens to achieve this with a theory derived from physics.
• The Role of Retinoic Acid in Tolerance and Immunity
  - Immunity 35(1):13-22 (2011)
  Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology.
• A Single T Cell Receptor Bound to Major Histocompatibility Complex Class I and Class II Glycoproteins Reveals Switchable TCR Conformers
  - Immunity 35(1):23-33 (2011)
  Major histocompatibility complex class I (MHCI) and MHCII proteins differ in structure and sequence. To understand how T cell receptors (TCRs) can use the same set of variable regions to bind both proteins, we have presented a comparison of a single TCR bound to both MHCI and MHCII ligands. The TCR adopts similar orientations on both ligands with TCR amino acids thought to be evolutionarily conserved for MHC interaction occupying similar positions on the MHCI and MHCII helices. However, the TCR antigen-binding loops use different conformations when interacting with each ligand. Most importantly, we observed alternate TCR core conformations. When bound to MHCI, but not MHCII, Vα disengages from the Jα β strand, switching Vα's position relative to Vβ. In several other structures, either Vα or Vβ undergoes this same modification. Thus, both TCR V-domains can switch among alternate conformations, perhaps extending their ability to react with different MHC-peptide li! gands.
• Anthrax Toxin Induces Macrophage Death by p38 MAPK Inhibition but Leads to Inflammasome Activation via ATP Leakage
  - Immunity 35(1):34-44 (2011)
  Detection of microbial constituents by membrane associated and cytoplasmic pattern recognition receptors is the essence of innate immunity, leading to activation of protective host responses. However, it is still unclear how immune cells specifically respond to pathogenic bacteria. Using virulent and nonvirulent strains of Bacillus anthracis, we have shown that secretion of ATP by infected macrophages and the sequential activation of the P2X7 purinergic receptor and nucleotide binding oligomerization domain (NOD)-like receptors are critical for IL-1-dependent host protection from virulent B. anthracis. Importantly, lethal toxin produced by virulent B. anthracis blocked activation of protein kinases, p38 MAPK and AKT, resulting in opening of a connexin ATP release channel and induction of macrophage death. Prevention of cell death or ATP release through constitutive p38 or AKT activation interfered with inflammasome activation and IL-1β production, thereby compromising! antimicrobial immunity.
• Signaling by the Phosphatase MKP-1 in Dendritic Cells Imprints Distinct Effector and Regulatory T Cell Fates
  - Immunity 35(1):45-58 (2011)
  Naive T cells respond to antigens by differentiating into effector and regulatory lineages. Whereas the roles of T cell-intrinsic pathways have been extensively studied, how T cell lineage choices are controlled by innate immune signals remains elusive. Here we report that dendritic cell (DC)-expressed phosphatase MKP-1, a negative regulator of the MAP kinases, programmed reciprocal T helper 1 (Th1) and Th17 cell differentiation by modulating IL-12-STAT4 and IL-6-STAT3 axes and cytokine receptor expression at the DC-T cell interface. MKP-1 was regulated by innate recognition signals and its deficiency disrupted antimicrobial responses and promoted T cell-mediated inflammation. Moreover, MKP-1 inhibited induction of regulatory T cells by downregulating TGF-β2 production from DCs. Our findings identify a regulatory circuit linking MKP-1 signaling in DCs, production of polarizing cytokines, and integration of DC-derived signals in responding T cells, that bridges innate ! and adaptive immunity to coordinate protective immunity and immunopathology.
• Skint-1 Identifies a Common Molecular Mechanism for the Development of Interferon-γ-Secreting versus Interleukin-17-Secreting γδ T Cells
  - Immunity 35(1):59-68 (2011)
  Murine T cell development begins with the generation of a unique Vγ5+Vδ1+ epidermal γδ T cell compartment and a unique, more broadly distributed Vγ6+Vδ1+ subset that is an important source of interleukin-17 (IL-17). This study showed that these respective functional programs were determined by Skint-1, a thymic epithelial cell determinant. By engaging Skint-1+ cells, Vγ5+Vδ1+ thymocytes induced an Egr3-mediated pathway, provoking differentiation and the potential to produce IFN-γ while suppressing the γδ T cell lineage factor, Sox13, and a RORγt transcription factor-associated IL-17-producing capacity. Hence, the functions of the earliest T cells are substantially preprogrammed in the thymus. Additionally, the phenotype of Skint-1-selected fetal thymocytes permitted identification in the adult thymus of an analogous gene regulatory network regulated by the γδ T cell receptor. Hence, these observations describe a molecular pathway by which distinct stress-! responsive lymphocyte repertoires may emerge throughout ontogeny and offer parallels with emerging perspectives on the functional selection of other lymphoid cells.
• Unc93B1 Restricts Systemic Lethal Inflammation by Orchestrating Toll-like Receptor 7 and 9 Trafficking
  - Immunity 35(1):69-81 (2011)
  Toll-like receptor-7 (TLR7) and 9, innate immune sensors for microbial RNA or DNA, have been implicated in autoimmunity. Upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, Unc93B1. Little is known, however, about a role for sensor transportation in controlling autoimmunity. TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7. TLR9 skewing is actively maintained by Unc93B1 and reversed to TLR7 if Unc93B1 loses preferential binding via a D34A mutation. We here demonstrate that mice harboring a D34A mutation showed TLR7-dependent, systemic lethal inflammation. CD4+ T cells showed marked differentiation toward T helper 1 (Th1) or Th17 cell subsets. B cell depletion abolished T cell differentiation and systemic inflammation. Thus, Unc93B1 controls homeostatic TLR7 activation by balancing TLR9 to TLR7 trafficking.
• The Ubiquitin-Editing Protein A20 Prevents Dendritic Cell Activation, Recognition of Apoptotic Cells, and Systemic Autoimmunity
  - Immunity 35(1):82-96 (2011)
  Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonical NF-κB activation. Tnfaip3fl/flCd11c-cre+ mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly—features of systemic lupus erythematosus—and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorp! hisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.
• The Costimulatory Molecule CD27 Maintains Clonally Diverse CD8+ T Cell Responses of Low Antigen Affinity to Protect against Viral Variants
  - Immunity 35(1):97-108 (2011)
  CD70 and CD27 are costimulatory molecules that provide essential signals for the expansion and differentiation of CD8+ T cells. Here, we show that CD27-driven costimulation lowered the threshold of T cell receptor activation on CD8+ T cells and enabled responses against low-affinity antigens. Using influenza infection to study in vivo consequences, we found that CD27-driven costimulation promoted a CD8+ T cell response of overall low affinity. These qualitative effects of CD27 on T cell responses were maintained into the memory phase. On a clonal level, CD27-driven costimulation established a higher degree of variety in memory CD8+ T cells. The benefit became apparent when mice were reinfected, given that CD27 improved CD8+ T cell responses against reinfection with viral variants, but not with identical virus. We propose that CD27-driven costimulation is a strategy to generate memory clones that have potential reactivity to a wide array of mutable pathogens.
• A Requisite Role for Induced Regulatory T Cells in Tolerance Based on Expanding Antigen Receptor Diversity
  - Immunity 35(1):109-122 (2011)
  Although both natural and induced regulatory T (nTreg and iTreg) cells can enforce tolerance, the mechanisms underlying their synergistic actions have not been established. We examined the functions of nTreg and iTreg cells by adoptive transfer immunotherapy of newborn Foxp3-deficient mice. As monotherapy, only nTreg cells prevented disease lethality, but did not suppress chronic inflammation and autoimmunity. Provision of Foxp3-sufficient conventional T cells with nTreg cells reconstituted the iTreg pool and established tolerance. In turn, acute depletion of iTreg cells in rescued mice resulted in weight loss and inflammation. Whereas the transcriptional signatures of nTreg and in vivo-derived iTreg cells were closely matched, there was minimal overlap in their T cell receptor (TCR) repertoires. Thus, iTreg cells are an essential nonredundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses.
• T Cell Surveillance of Oncogene-Induced Prostate Cancer Is Impeded by T Cell-Derived TGF-β1 Cytokine
  - Immunity 35(1):123-134 (2011)
  Tolerance induction in T cells takes place in most tumors and is thought to account for tumor evasion from immune eradication. Production of the cytokine TGF-β is implicated in immunosuppression, but the cellular mechanism by which TGF-β induces T cell dysfunction remains unclear. With a transgenic model of prostate cancer, we showed that tumor development was not suppressed by the adaptive immune system, which was associated with heightened TGF-β signaling in T cells from the tumor-draining lymph nodes. Blockade of TGF-β signaling in T cells enhanced tumor antigen-specific T cell responses and inhibited tumor development. Surprisingly, T cell- but not Treg cell-specific ablation of TGF-β1 was sufficient to augment T cell cytotoxic activity and blocked tumor growth and metastases. These findings reveal that T cell production of TGF-β1 is an essential requirement for tumors to evade immunosurveillance independent of TGF-β produced by tumors.
• Innate Immune Sensing of Retroviral Infection via Toll-like Receptor 7 Occurs upon Viral Entry
  - Immunity 35(1):135-145 (2011)
  Innate immune sensors are required for induction of pathogen-specific immune responses. Retroviruses are notorious for their ability to evade immune defenses and establish long-term persistence in susceptible hosts. However, some infected animals are able to develop efficient virus-specific immune responses, and thus can be employed for identification of critical innate virus-sensing mechanisms. With mice from two inbred strains that control retroviruses via adaptive immune mechanisms, we found that of all steps in viral replication, the ability to enter the host cell was sufficient to induce antivirus humoral immune responses. Virus sensing occurred in endosomes via a MyD88-Toll-like receptor 7-dependent mechanism and stimulated virus-neutralizing immunity independently of type I interferons. Thus, efficient adaptive immunity to retroviruses is induced in vivo by innate sensing of the early stages of retroviral infection.
• The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock
  - Immunity 35(1):146 (2011)
  

Hot off the presses! Jan 28 Immunity

The Jan 28 issue of the Immunity is now up on Pubget (About Immunity): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Late Arrival: Recruiting Coreceptors to the T Cell Receptor Complex
  - Immunity 34(1):1-3 (2011)
  In this issue of Immunity, Jiang et al. (2011) provide evidence that the CD8 coreceptor is recruited to the T cell receptor (TCR) complex after initial TCR triggering where it stabilizes the TCR-peptide-major histocompatibility complex interaction.
• CNS Autoimmune Inflammation: RICK Must NOD!
  - Immunity 34(1):3-5 (2011)
  In this issue of Immunity, Shaw et al. (2011) report that the NOD-RICK signaling axis is required for the activation of dendritic cells infiltrating the central nervous system, leading to reactivation of antigen-specific T cells and autoimmune inflammation.
• Erythropoietin Surprises: An Immune Saga
  - Immunity 34(1):6-7 (2011)
  Erythropoietin (EPO) an erythropoietic stimulating agent also exerts effects on other cell systems. Nairz et al. (2011) now link EPO and intracellular signaling through the EPO receptor (EPOR) to innate immune cell activity via macrophages.
• Deflating the Lymph Node
  - Immunity 34(1):8-10 (2011)
  Although the lymph node lymphatic vessel growth and development is positively regulated by B cells and macrophages, Kataru et al. (2011), in this issue of Immunity, show negative regulation of lymphatic vessels by interferon-γ from T cells.
• Blood Relatives of Follicular Helper T Cells
  - Immunity 34(1):10-12 (2011)
  Expression of the chemokine receptor CXCR5 identifies B follicular helper T cells. In this issue of Immunity, Morita et al. (2011) describe a heterogeneous circulating CXCR5+CD4+ B cell helper population overrepresented in juvenile dermatomyositis patients.
• Two-Stage Cooperative T Cell Receptor-Peptide Major Histocompatibility Complex-CD8 Trimolecular Interactions Amplify Antigen Discrimination
  - Immunity 34(1):13-23 (2011)
  The T cell receptor (TCR) and CD8 bind peptide-major histocompatibility complex (pMHC) glycoproteins to initiate adaptive immune responses, yet the trimolecular binding kinetics at the T cell membrane is unknown. By using a micropipette adhesion frequency assay, we show that this kinetics has two stages. The first consists of TCR-dominant binding to agonist pMHC. This triggers a second stage consisting of a step increase in adhesion after a one second delay. The second-stage binding requires Src family kinase activity to initiate CD8 binding to the same pMHC engaged by the TCR. This induced trimeric-cooperative interaction enhances adhesion synergistically to favor potent ligands, which further amplifies discrimination. Our data reveal a TCR-CD8 positive-feedback loop involved in initial signaling steps that is sensitive to a single pMHC is rapid, reversible, synergistic, and peptide discriminative.
• Deficiency of Rap1-Binding Protein RAPL Causes Lymphoproliferative Disorders through Mislocalization of p27kip1
  - Immunity 34(1):24-38 (2011)
  RAPL (an alternative spliced form of Rassf5) is a critical Ras-related protein1 (Rap1) effector that regulates lymphocyte adhesion. Here, we have shown that in addition to this previously described function, RAPL also negatively controls lymphocyte proliferation and prevents autoimmunity and lymphoma. RAPL-deficient mice experienced age-related lupus-like glomerulonephritis and developed B cell lymphomas. RAPL-deficient lymphocytes showed hyperproliferation by enhanced S phase entry after antigen receptor ligation. Compared to wild-type cells, RAPL-deficient naive lymphocytes had a 2- to 3-fold increase in Cdk2 kinase activity with a cytoplasmic mislocalization of the cyclin-dependent kinase inhibitor p27kip1. RAPL was found to suppress the phosphorylation of p27kip1 on serine 10 (S10) and promoted p27kip1 nuclear translocation. An S10A mutation in p27kip1 corrected its cytoplasmic accumulation, reduced hyperproliferation in RAPL-deficient lymphocytes, and suppressed g! lomerulonephritis and development of B cell lymphoma. Thus, RAPL serves as a checkpoint for S phase entry to prevent lymphoproliferative disorders through the spatial regulation of p27kip1.
• The Transcription Factor STAT3 Is Required for T Helper 2 Cell Development
  - Immunity 34(1):39-49 (2011)
  Signal transducer and activator of transcription (STAT) family members direct the differentiation of T helper cells, with specific STAT proteins promoting distinct effector subsets. STAT6 is required for the development of T helper 2 (Th2) cells, whereas STAT3 promotes differentiation of Th17 and follicular helper T cell subsets. We demonstrated that STAT3 was also activated during Th2 cell development and was required for the expression of Th2 cell-associated cytokines and transcription factors. STAT3 bound directly to Th2 cell-associated gene loci and was required for the ability of STAT6 to bind target genes. In vivo, STAT3 deficiency in T cells eliminated the allergic inflammation in mice sensitized and challenged with ovalbumin or transgenic for constitutively active STAT6. Thus, STAT3 cooperates with STAT6 in promoting Th2 cell development. These results demonstrate that differentiating T helper cells integrate multiple STAT protein signals during Th2 cell develo! pment.
• Posttranscriptional Silencing of Effector Cytokine mRNA Underlies the Anergic Phenotype of Self-Reactive T Cells
  - Immunity 34(1):50-60 (2011)
  Self-reactive T cell clones that escape negative selection are either deleted or rendered functionally unresponsive (anergic), thus preventing them from propagating host tissue damage. By using an in vivo model, we investigated molecular mechanisms for T cell tolerance, finding that despite a characteristic inability to generate effector cytokine proteins, self-reactive T cells express large amounts of cytokine mRNAs. This disconnect between cytokine message and protein was not observed in T cells mounting productive responses to foreign antigens but, instead, was seen only in those responding to self, where the block in protein translation was shown to involve conserved AU-rich elements within cytokine 3′UTRs. These studies reveal that translation of abundant cytokine mRNAs is limited in self-reactive T cells and, thus, identify posttranscriptional silencing of antigen-driven gene expression as a key mechanism underlying the anergic phenotype of self-reactive T cell! s.
• Erythropoietin Contrastingly Affects Bacterial Infection and Experimental Colitis by Inhibiting Nuclear Factor-κB-Inducible Immune Pathways
  - Immunity 34(1):61-74 (2011)
  Erythropoietin (EPO) is the principal cytokine regulating erythropoiesis through its receptor, EPOR. Interestingly, EPORs are also found on immune cells with incompletely understood functions. Here, we show that EPO inhibits the induction of proinflammatory genes including tumor necrosis factor (TNF)-α and inducible nitric oxide (NO) synthase in activated macrophages, which is mechanistically attributable to blockage of nuclear factor (NF)-κB p65 activation by EPO. Accordingly, in systemic Salmonella infection, treatment of mice with EPO results in reduced survival and impaired pathogen clearance because of diminished formation of anti-microbial effector molecules such as TNF-α and NO. However, neutralization of endogenous EPO or genetic ablation of Epor promotes Salmonella elimination. In contrast, in chemically induced colitis, EPO-EPOR interaction decreases the production of NF-κB-inducible immune mediators, thus limiting tissue damage and ameliorating disease s! everity. These immune-modulatory effects of EPO may be of therapeutic relevance in infectious and inflammatory diseases.
• Signaling via the RIP2 Adaptor Protein in Central Nervous System-Infiltrating Dendritic Cells Promotes Inflammation and Autoimmunity
  - Immunity 34(1):75-84 (2011)
  Peripheral peptidolgycan (PGN) is present within antigen-presenting cells in the central nervous system (CNS) of multiple sclerosis (MS) patients, possibly playing a role in neuroinflammation. Accordingly, PGN is linked with disease progression in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), but the role of specific PGN-sensing proteins is unknown. Here we report that the progression of EAE was dependent on the intracellular PGN sensors NOD1 and NOD2 and their common downstream adaptor molecule, receptor interacting protein 2 (RIP2; also known as RIPK2 and RICK). We found that RIP2, but not toll-like receptor 2 (TLR2), played a critical role in the activation of CNS-infiltrating dendritic cells. Our results suggest that PGN in the CNS is involved in the pathogenesis of EAE through the activation of infiltrating dendritic cells via NOD1-, NOD2-, and RIP2-mediated pathways.
• CD169-Positive Macrophages Dominate Antitumor Immunity by Crosspresenting Dead Cell-Associated Antigens
  - Immunity 34(1):85-95 (2011)
  The generation of tumor-directed cytotoxic T lymphocytes is considered crucial for the induction of antitumor immunity. To activate these CD8+ T cells, antigen-presenting cells (APCs) must initially acquire tumor cell-associated antigens. The major source of tumor antigens is dead tumor cells, but little is known about how APCs in draining lymph nodes acquire and crosspresent these antigens. Here we show that CD169+ macrophages phagocytose dead tumor cells transported via lymphatic flow and subsequently crosspresent tumor antigens to CD8+ T cells. Subcutaneous immunization with irradiated tumor cells protects mice from syngenic tumor. However, tumor antigen-specific CD8+ T cell activation and subsequent antitumor immunity are severely impaired in mice depleted with CD169+ macrophages. Neither migratory dendritic cells (DCs) nor lymph node-resident conventional DCs are essential for the crosspresentation of tumor antigens. Thus, we have identified CD169+ macrophages as ! lymph node-resident APCs dominating early activation of tumor antigen-specific CD8+ T cells.
• T Lymphocytes Negatively Regulate Lymph Node Lymphatic Vessel Formation
  - Immunity 34(1):96-107 (2011)
  Lymph node lymphatic vessels (LNLVs) serve as a conduit to drain antigens from peripheral tissues to within the lymph nodes. LNLV density is known to be positively regulated by vascular endothelial growth factors secreted by B cells, macrophages, and dendritic cells (DCs). Here, we show that LNLV formation was negatively regulated by T cells. In both steady and inflammatory states, the density of LNLVs was increased in the absence of T cells but decreased when T cells were restored. Interferon-γ secretion by T cells suppressed lymphatic-specific genes in lymphatic endothelial cells and consequently caused marked reduction in LNLV formation. When T cells were depleted, recruitment of antigen-carrying DCs to LNs was augmented, reflecting a compensatory mechanism for antigen presentation to T cells through increased LNLVs. Thus, T cells maintain the homeostatic balance of LNLV density through a negative paracrine action of interferon-γ.
• Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion
  - Immunity 34(1):108-121 (2011)
  Although a fraction of human blood memory CD4+ T cells expresses chemokine (C-X-C motif) receptor 5 (CXCR5), their relationship to T follicular helper (Tfh) cells is not well established. Here we show that human blood CXCR5+CD4+ T cells share functional properties with Tfh cells and appear to represent their circulating memory compartment. Blood CXCR5+CD4+ T cells comprised three subsets: T helper 1 (Th1), Th2, and Th17 cells. Th2 and Th17 cells within CXCR5+, but not within CXCR5−, compartment efficiently induced naive B cells to produce immunoglobulins via interleukin-21 (IL-21). In contrast, Th1 cells from both CXCR5+ and CXCR5− compartments lacked the capacity to help B cells. Patients with juvenile dermatomyositis, a systemic autoimmune disease, displayed a profound skewing of blood CXCR5+ Th cell subsets toward Th2 and Th17 cells. Importantly, the skewing of subsets correlated with disease activity and frequency of blood plasmablasts. Collectively, our study ! suggests that an altered balance of Tfh cell subsets contributes to human autoimmunity.
• CD4+ Lymphoid Tissue-Inducer Cells Promote Innate Immunity in the Gut
  - Immunity 34(1):122-134 (2011)
  Fetal CD4+ lymphoid tissue inducer (LTi) cells play a critical role in the development of lymphoid tissues. Recent studies identified that LTi cells persist in adults and are related to a heterogeneous population of innate lymphoid cells that have been implicated in inflammatory responses. However, whether LTi cells contribute to protective immunity remains poorly defined. We demonstrate that after infection with Citrobacter rodentium, CD4+ LTi cells were a dominant source of interleukin-22 (IL-22) early during infection. Infection-induced CD4+ LTi cell responses were IL-23 dependent, and ablation of IL-23 impaired innate immunity. Further, depletion of CD4+ LTi cells abrogated infection-induced expression of IL-22 and antimicrobial peptides, resulting in exacerbated host mortality. LTi cells were also found to be essential for host protective immunity in lymphocyte-replete hosts. Collectively these data demonstrate that adult CD4+ LTi cells are a critical source of IL! -22 and identify a previously unrecognized function for CD4+ LTi cells in promoting innate immunity in the intestine.
• Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion
  - Immunity 34(1):135 (2011)
  
• Foxo Transcription Factors Control Regulatory T Cell Development and Function
  - Immunity 34(1):135 (2011)
  

Hot off the presses! Oct 29 Immunity

The Oct 29 issue of the Immunity is now up on Pubget (About Immunity): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• A Decade of Vaccines: Integrating Immunology and Vaccinology for Rational Vaccine Design
  - Immunity 33(4):437-440 (2010)
  Vaccination stands as one of the most successful public health measures of the last century. New approaches will be needed, however, to develop highly effective vaccines to prevent tuberculosis, HIV-AIDS, and malaria and to eradicate polio. Current advances in immunology and technology have set the stage for rational vaccine design to begin a "Decade of Vaccines."
• Vaccines and the Future of Human Immunology
  - Immunity 33(4):441-450 (2010)
  In this issue of Immunity, a collection of detailed reviews summarizes needs, opportunities, and roadblocks to the development of new vaccines, all in the context of our current knowledge and understanding of key aspects of immune function and microbial interactions with the host. This Perspective is designed to provide a broad overview that discusses our present limitations in designing effective novel vaccines for diseases that do not typically induce robust resistance in infected individuals and how the addition of a systems-level, multiplexed approach to the analysis of the human immune system can complement traditional highly focused research efforts to accelerate our progress toward this goal and the improvement of human health.
• From Vaccines to Memory and Back
  - Immunity 33(4):451-463 (2010)
  Vaccines work by eliciting an immune response and consequent immunological memory that mediates protection from infection or disease. Recently, new methods have been developed to dissect the immune response in experimental animals and humans, which have led to increased understanding of the molecular mechanisms that control differentiation and maintenance of memory T and B cells. In this review we will provide an overview of the cellular organization of immune memory and underline some of the outstanding questions on immunological memory and how they pertain to vaccination strategies. Finally we will discuss how we can learn about antigen design from the interrogation of our memory T and B cells—a journey from vaccines to memory and back.
• Designing Vaccines Based on Biology of Human Dendritic Cell Subsets
  - Immunity 33(4):464-478 (2010)
  The effective vaccines developed against a variety of infectious agents, including polio, measles, and hepatitis B, represent major achievements in medicine. These vaccines, usually composed of microbial antigens, are often associated with an adjuvant that activates dendritic cells (DCs). Many infectious diseases are still in need of an effective vaccine including HIV, malaria, hepatitis C, and tuberculosis. In some cases, the induction of cellular rather than humoral responses may be more important because the goal is to control and eliminate the existing infection rather than to prevent it. Our increased understanding of the mechanisms of antigen presentation, particularly with the description of DC subsets with distinct functions, as well as their plasticity in responding to extrinsic signals, represent opportunities to develop novel vaccines. In addition, we foresee that this increased knowledge will permit us to design vaccines that will reprogram the immune syste! m to intervene therapeutically in cancer, allergy, and autoimmunity.
• Vaccination Strategies to Promote Mucosal Antibody Responses
  - Immunity 33(4):479-491 (2010)
  There are great interest and demand for the development of vaccines to prevent and treat diverse microbial infections. Mucosal vaccines elicit immune protection by stimulating the production of antibodies at mucosal surfaces and systemic districts. Being positioned in close proximity to a large community of commensal microbes, the mucosal immune system deploys a heterogeneous population of cells and a complex regulatory network to maintain the balance between surveillance and tolerance. A successful mucosal vaccine relies on leveraging the functions of these immune cells and regulatory components. We review the important cellular interactions and molecular pathways underlying the induction and regulation of mucosal antibody responses and discuss their implications on mucosal vaccination.
• Vaccine Adjuvants: Putting Innate Immunity to Work
  - Immunity 33(4):492-503 (2010)
  Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens.
• Immunologic Basis of Vaccine Vectors
  - Immunity 33(4):504-515 (2010)
  Efforts to make vaccines against infectious diseases as well as immunotherapies for cancer, autoimmune diseases and allergy have utilized a variety of heterologous expression systems, including viral and bacterial vectors, as well as DNA and RNA constructs. This review explores the immunologic rationale and provides an update of insights obtained from preclinical and clinical studies of such vaccines.
• Systems Vaccinology
  - Immunity 33(4):516-529 (2010)
  Vaccination is one of the greatest triumphs of modern medicine, yet we remain largely ignorant of the mechanisms by which successful vaccines stimulate protective immunity. Two recent advances are beginning to illuminate such mechanisms: realization of the pivotal role of the innate immune system in sensing microbes and stimulating adaptive immunity, and advances in systems biology. Recent studies have used systems biology approaches to obtain a global picture of the immune responses to vaccination in humans. This has enabled the identification of early innate signatures that predict the immunogenicity of vaccines, and identification of potentially novel mechanisms of immune regulation. Here, we review these advances and critically examine the potential opportunities and challenges posed by systems biology in vaccine development.
• Reverse Vaccinology: Developing Vaccines in the Era of Genomics
  - Immunity 33(4):530-541 (2010)
  The sequence of microbial genomes made all potential antigens of each pathogen available for vaccine development. This increased by orders of magnitude potential vaccine targets in bacteria, parasites, and large viruses and revealed virtually all their CD4+ and CD8+ T cell epitopes. The genomic information was first used for the development of a vaccine against serogroup B meningococcus, and it is now being used for several other bacterial vaccines. In this review, we will first summarize the impact that genome sequencing has had on vaccine development, and then we will analyze how the genomic information can help further our understanding of immunity to infection or vaccination and lead to the design of better vaccines by diving into the world of T cell immunity.
• Induction of Immunity to Human Immunodeficiency Virus Type-1 by Vaccination
  - Immunity 33(4):542-554 (2010)
  Recent findings have brought optimism that development of a successful human immunodeficiency virus type-1 (HIV-1) vaccine lies within reach. Studies of early events in HIV-1 infection have revealed when and where HIV-1 is potentially vulnerable to vaccine-targeted immune responses. With technical advances in human antibody production, clues about how antibodies recognize HIV-1 envelope proteins have uncovered new targets for immunogen design. A recent vaccine regimen has shown modest efficacy against HIV-1 acquisition. However, inducing long-term T and B cell memory and coping with HIV-1 diversity remain high priorities. Mediators of innate immunity may play pivotal roles in blocking infection and shaping immunity; vaccine strategies to capture these activities are under investigation. Challenges remain in integrating basic, preclinical and clinical research to improve predictions of types of immunity associated with vaccine efficacy, to apply these insights to immuno! gen design, and to accelerate evaluation of vaccine efficacy in persons at-risk for infection.
• Malaria Vaccine Design: Immunological Considerations
  - Immunity 33(4):555-566 (2010)
  The concept of a malaria vaccine has sparked great interest for decades; however, the challenge is proving to be a difficult one. Immune dysregulation by Plasmodium and the ability of the parasite to mutate critical epitopes in surface antigens have proved to be strong defense weapons. This has led to reconsideration of polyvalent and whole parasite strategies and ways to enhance cellular immunity to malaria that may be more likely to target conserved antigens and an expanded repertoire of antigens. These and other concepts will be discussed in this review.
• Future Vaccination Strategies against Tuberculosis: Thinking outside the Box
  - Immunity 33(4):567-577 (2010)
  With almost a dozen vaccine candidates in clinical trials, tuberculosis (TB) research and development is finally reaping the first fruits of its labors. Vaccine candidates in clinical trials may prevent TB disease reactivation by efficiently containing the pathogen Mycobacterium tuberculosis (Mtb). Future research should target vaccines that achieve sterile eradication of Mtb or even prevent stable infection. These are ambitious goals that can be reached only by highly cooperative engagement of basic immunologists, vaccinologists, and clinical researchers—or in other words, by translation from basic immunology to vaccine research and development, as well as reverse translation of insights from clinical trials back to hypothesis-driven research in the basic laboratory. Here, we review current and future strategies toward the rational design of novel vaccines against TB, as well as the progress made thus far, and the hurdles that need to be overcome in the near and dis! tant future.
• Recycling Endosomes and TLR Signaling— The Rab11 GTPase Leads the Way
  - Immunity 33(4):578-580 (2010)
  The ability of Toll-like receptors (TLRs) to activate innate immunity depends on their transport to pathogen-containing organelles. In this issue of Immunity, Husebye et al. (2010) report that delivery of TLR4 to phagosomes occurs via a recycling endosome intermediate, which is controlled by the GTPase Rab11a.
• A Flt3L Encounter: mTOR Signaling in Dendritic Cells
  - Immunity 33(4):580-582 (2010)
  The signaling pathway of the cytokine Flt3L in dendritic cells (DCs) is poorly defined. In this issue of Immunity, Sathaliyawala et al. (2010) report that the kinase mTOR functions as a mediator of Flt3L signaling in the development and homeostasis of DCs, particularly of the CD8+ and CD103+ DCs.
• The Rab11a GTPase Controls Toll-like Receptor 4-Induced Activation of Interferon Regulatory Factor-3 on Phagosomes
  - Immunity 33(4):583-596 (2010)
  Toll-like receptor 4 (TLR4) is indispensable for recognition of Gram-negative bacteria. We described a trafficking pathway for TLR4 from the endocytic recycling compartment (ERC) to E. coli phagosomes. We found a prominent colocalization between TLR4 and the small GTPase Rab11a in the ERC, and Rab11a was involved in the recruitment of TLR4 to phagosomes in a process requiring TLR4 signaling. Also, Toll-receptor-associated molecule (TRAM) and interferon regulatory factor-3 (IRF3) localized to E. coli phagosomes and internalization of E. coli was required for a robust interferon-β induction. Suppression of Rab11a reduced TLR4 in the ERC and on phagosomes leading to inhibition of the IRF3 signaling pathway induced by E. coli, whereas activation of the transcription factor NF-κB was unaffected. Moreover, Rab11a silencing reduced the amount of TRAM on phagosomes. Thus, Rab11a is an important regulator of TLR4 and TRAM transport to E. coli phagosomes thereby controlling IR! F3 activation from this compartment.
• Mammalian Target of Rapamycin Controls Dendritic Cell Development Downstream of Flt3 Ligand Signaling
  - Immunity 33(4):597-606 (2010)
  Dendritic cells (DCs) comprise distinct functional subsets including CD8− and CD8+ classical DCs (cDCs) and interferon-secreting plasmacytoid DCs (pDCs). The cytokine Flt3 ligand (Flt3L) controls the development of DCs and is particularly important for the pDC and CD8+ cDC and their CD103+ tissue counterparts. We report that mammalian target of rapamycin (mTOR) inhibitor rapamycin impaired Flt3L-driven DC development in vitro, with the pDCs and CD8+-like cDCs most profoundly affected. Conversely, deletion of the phosphoinositide 3-kinase (PI3K)-mTOR negative regulator Pten facilitated Flt3L-driven DC development in culture. DC-specific Pten targeting in vivo caused the expansion of CD8+ and CD103+ cDC numbers, which was reversible by rapamycin. The increased CD8+ cDC numbers caused by Pten deletion correlated with increased susceptibility to the intracellular pathogen Listeria. Thus, PI3K-mTOR signaling downstream of Flt3L controls DC development, and its restriction! by Pten ensures optimal DC pool size and subset composition.
• MicroRNA-155 Promotes Autoimmune Inflammation by Enhancing Inflammatory T Cell Development
  - Immunity 33(4):607-619 (2010)
  Mammalian noncoding microRNAs (miRNAs) are a class of gene regulators that have been linked to immune system function. Here, we have investigated the role of miR-155 during an autoimmune inflammatory disease. Consistent with a positive role for miR-155 in mediating inflammatory responses, Mir155−/− mice were highly resistant to experimental autoimmune encephalomyelitis (EAE). miR-155 functions in the hematopoietic compartment to promote the development of inflammatory T cells including the T helper 17 (Th17) cell and Th1 cell subsets. Furthermore, the major contribution of miR-155 to EAE was CD4+ T cell intrinsic, whereas miR-155 was also required for optimum dendritic cell production of cytokines that promoted Th17 cell formation. Our study shows that one aspect of miR-155 function is the promotion of T cell-dependent tissue inflammation, suggesting that miR-155 might be a promising therapeutic target for the treatment of autoimmune disorders.
• Carcinoembryonic Antigen-Related Cell Adhesion Molecule-1 Regulates Granulopoiesis by Inhibition of Granulocyte Colony-Stimulating Factor Receptor
  - Immunity 33(4):620-631 (2010)
  Although carcinoembryonic antigen-related cell adhesion moclecule-1 (CEACAM1) is an activation marker for neutrophils and delays neutrophil apoptosis, the role of CEACAM1 in granulopoiesis and neutrophil-dependent host immune responses has not been investigated. CEACAM1 expression correlated with granulocytic differentiation, and Ceacam1−/− mice developed neutrophilia because of loss of the Src-homology-phosphatase-1 (SHP-1)-dependent inhibition of granulocyte colony-stimulating factor receptor (G-CSFR) signal transducer and activator of transcription (Stat3) pathway provided by CEACAM1. Moreover, Ceacam1−/− mice were hypersensitive to Listeria Monocytogenes (LM) infection with an accelerated mortality. Reintroduction of CEACAM1 into Ceacam1−/− bone marrow restored normal granulopoiesis and host sensitivity to LM infection, while mutation of its immunoreceptor tyrosine-based inhibitory motifs (ITIMs) abrogated this restoration. shRNA-mediated reduction of S! tat3 amounts rescued normal granulopoiesis, attenuating host sensitivity to LM infection in Ceacam1−/− mice. Thus, CEACAM1 acted as a coinhibitory receptor for G-CSFR regulating granulopoiesis and host innate immune response to bacterial infections.
• Intravital Imaging Reveals Distinct Dynamics for Natural Killer and CD8+ T Cells during Tumor Regression
  - Immunity 33(4):632-644 (2010)
  Recognition of NKG2D ligands by natural killer (NK) cells plays an important role during antitumoral responses. To address how NKG2D engagement affects intratumoral NK cell dynamics, we performed intravital microscopy in a Rae-1β-expressing solid tumor. This NKG2D ligand drove NK cell accumulation, activation, and motility within the tumor. NK cells established mainly dynamic contacts with their targets during tumor regression. In sharp contrast, cytotoxic T lymphocytes (CTLs) formed stable contacts in tumors expressing their cognate antigen. Similar behaviors were observed during effector functions in lymph nodes. In vitro, contacts between NK cells and their targets were cytotoxic but did not elicit sustained calcium influx nor adhesion, whereas CTL contact stability was critically dependent on extracellular calcium entry. Altogether, our results offer mechanistic insight into how NK cells and CTLs can exert cytotoxic activity with remarkably different contact dynam! ics.

Hot off the presses! Apr 22 Immunity

The Apr 22 issue of the Immunity is now up on Pubget (About Immunity): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Jürg Tschopp (1951–2011)
  - Immunity 34(4):451-452 (2011)
  
• Special Delivery: Granulin Brings CpG DNA to Toll-like Receptor 9
  - Immunity 34(4):453-455 (2011)
  Foreign DNA activates the innate immune response through Toll-like receptor 9 (TLR9). In this issue of Immunity, Park et al. (2011) present evidence that granulin is a cofactor for TLR9 activation, delivering CpG-oligodeoxynucleotides to TLR9 in endolysosomes.
• Getting Closer to the Dirty Little Secret
  - Immunity 34(4):455-458 (2011)
  The molecular mechanism behind alum adjuvanticity is probably the oldest secret of immunology. In this issue of Immunity, Kuroda et al. (2011) and Kool et al. (2011) identify NLRP3 inflammasome-independent signaling to be crucial for the Th2 cell response induced by aluminum salts.
• Resistance to Mousepox Virus: CD94 on a Special Mission
  - Immunity 34(4):458-460 (2011)
  NK cells play a key role in the control of ectromelia virus. In this issue of Immunity, Fang et al. (2011) demonstrate that the deletion of CD94 abolishes resistance to mousepox infection.
• At 17, In-10's Passion Need Not Inflame
  - Immunity 34(4):460-462 (2011)
  In this issue of Immunity, Chaudhry et al. (2011) and Huber et al. (2011) report that control of Th17 cell responses during colonic inflammation requires direct signaling by IL-10 in regulatory T cells and Th17 cells.
• Emergency Evacuation! Hematopoietic Niches Induce Cell Exit in Infection
  - Immunity 34(4):463-465 (2011)
  The roles of hematopoietic stem and/or progenitor cell niches during infection remain unclear. In this issue of Immunity, Shi et al. (2011) reveal that these niches upregulate MCP1 chemokine expression, inducing emigration of bone marrow monocytes into the circulation via the endothelium.
• Cell Surface Signaling Molecules in the Control of Immune Responses: A Tide Model
  - Immunity 34(4):466-478 (2011)
  A large numbers of cell surface signaling molecules (CSSMs) have been molecularly identified and functionally characterized in recent years and, via these studies, our knowledge in the control of immune response has increased exponentially. Two major lines of evidence emerge. First, the majority of immune cells rely on one or few CSSMs to deliver a primary triggering signal to sense their environment, leading to initiation of an immune response. Second, both costimulatory CSSMs that promote the response, and coinhibitory CSSMs that inhibit the response, are required to control direction and magnitude of a given immune response. With such tight feedback, immune responses are tuned and returned to baseline. These findings extend well beyond our previous observation in the requirement for lymphocyte activation and argue a revisit of the traditional "two-signal model" for activation and tolerance of lymphocytes. Here we propose a "tide" model to accommodate and int! erpret current experimental findings.
• Structure of a Domain-Swapped FOXP3 Dimer on DNA and Its Function in Regulatory T Cells
  - Immunity 34(4):479-491 (2011)
  The transcription factor FOXP3 is essential for the suppressive function of regulatory T cells that are required for maintaining self-tolerance. We have solved the crystal structure of the FOXP3 forkhead domain as a ternary complex with the DNA-binding domain of the transcription factor NFAT1 and a DNA oligonucleotide from the interleukin-2 promoter. A striking feature of this structure is that FOXP3 forms a domain-swapped dimer that bridges two molecules of DNA. Structure-guided or autoimmune disease (IPEX)-associated mutations in the domain-swap interface diminished dimer formation by the FOXP3 forkhead domain without compromising FOXP3 DNA binding. These mutations also eliminated T cell-suppressive activity conferred by FOXP3, both in vitro and in a murine model of autoimmune diabetes in vivo. We conclude that FOXP3-mediated suppressor function requires dimerization through the forkhead domain and that mutations in the dimer interface can lead to the systemic autoim! munity observed in IPEX patients.
• Asymmetric Proteasome Segregation as a Mechanism for Unequal Partitioning of the Transcription Factor T-bet during T Lymphocyte Division
  - Immunity 34(4):492-504 (2011)
  Polarized segregation of proteins in T cells is thought to play a role in diverse cellular functions including signal transduction, migration, and directed secretion of cytokines. Persistence of this polarization can result in asymmetric segregation of fate-determining proteins during cell division, which may enable a T cell to generate diverse progeny. Here, we provide evidence that a lineage-determining transcription factor, T-bet, underwent asymmetric organization in activated T cells preparing to divide and that it was unequally partitioned into the two daughter cells. This unequal acquisition of T-bet appeared to result from its asymmetric destruction during mitosis by virtue of concomitant asymmetric segregation of the proteasome. These results suggest a mechanism by which a cell may unequally localize cellular activities during division, thereby imparting disparity in the abundance of cell fate regulators in the daughter cells.
• Granulin Is a Soluble Cofactor for Toll-like Receptor 9 Signaling
  - Immunity 34(4):505-513 (2011)
  Toll-like receptor (TLR) signaling plays a critical role in innate and adaptive immune responses and must be tightly controlled. TLR4 uses LPS binding protein, MD-2, and CD14 as accessories to respond to LPS. We therefore investigated the presence of an analagous soluble cofactor that might assist in the recruitment of CpG oligonucleotides (CpG-ODNs) to TLR9. We report the identification of granulin as an essential secreted cofactor that potentiates TLR9-driven responses to CpG-ODNs. Granulin, an unusual cysteine-rich protein, bound to CpG-ODNs and interacted with TLR9. Macrophages from granulin-deficient mice showed not only impaired delivery of CpG-ODNs to endolysosomal compartments, but also decreased interaction of TLR9 with CpG-ODNs. As a consequence, granulin-deficient macrophages showed reduced responses to stimulation with CpG-ODNs, a trait corrected by provision of exogenous granulin. Thus, we propose that granulin contributes to innate immunity as a critical ! soluble cofactor for TLR9 signaling.
• Silica Crystals and Aluminum Salts Regulate the Production of Prostaglandin in Macrophages via NALP3 Inflammasome-Independent Mechanisms
  - Immunity 34(4):514-526 (2011)
  Particulates such as silica crystal (silica) and aluminum salts (alum) activate the inflammasome and induce the secretion of proinflammatory cytokines in macrophages. These particulates also induce the production of immunoglobulin E via a T helper 2 (Th2) cell-associated mechanism. However, the mechanism involved in the induction of type 2 immunity has not been elucidated. Here, we showed that silica and alum induced lipopolysaccharide-primed macrophages to produce the lipid mediator prostaglandin E2 (PGE2) and interleukin-1β (IL-1β). Macrophages deficient in the inflammasome components caspase 1, NALP3, and ASC revealed that PGE2 production was independent of the NALP3 inflammasome. PGE2 expression was markedly reduced in PGE synthase-deficient (Ptges−/−) macrophages, and Ptges−/−mice displayed reduced antigen-specific serum IgE concentrations after immunization with alum or silica. Our results indicate that silica and alum regulate the production of PGE2 an! d that the induction of PGE2 by particulates controls the immune response in vivo.
• An Unexpected Role for Uric Acid as an Inducer of T Helper 2 Cell Immunity to Inhaled Antigens and Inflammatory Mediator of Allergic Asthma
  - Immunity 34(4):527-540 (2011)
  Although deposition of uric acid (UA) crystals is known as the cause of gout, it is unclear whether UA plays a role in other inflammatory diseases. We here have shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allergen. Conversely, administration of UA crystals together with protein antigen was sufficient to promote Th2 cell immunity and features of asthma. The adjuvant effects of UA did not require the inflammasome (Nlrp3, Pycard) or the interleukin-1 (Myd88, IL-1r) axis. UA crystals promoted Th2 cell immunity by activating dendritic cells through spleen tyrosine kinase and PI3-kinase δ signaling. These findings provide further molecular insight into Th2 cell development and identify UA as an essential initiator and amplifier of allergic i! nflammation.
• A Central Role for mTOR Kinase in Homeostatic Proliferation Induced CD8+ T Cell Memory and Tumor Immunity
  - Immunity 34(4):541-553 (2011)
  The cell-intrinsic mechanisms guiding naive CD8+ T cells for clonal expansion and memory generation via homeostatic proliferation (HP) are unclear. Here, we have shown that HP of naive CD8+ T cells requires IL-7-, but not IL-15-induced mTOR kinase activation. HP-induced mTOR enhances transcription factor T-bet for functional maturation and CD122 expression, which sensitizes for an IL-15-dependent memory transition by favoring transcription factor Eomesodermin over T-bet. Inhibition of mTOR blocks T-bet and CD122 expression but preserves memory in an IL-15-independent manner by promoting Eomesodermin expression. The ability of rapamycin to augment HP-induced memory was cell-intrinsic given that silencing mTOR in CD8+ T cells generated identical outcomes. Strikingly, HP-induced CD8+ T cell memory generated by IL-15-dependent or -independent mechanisms demonstrated identical tumor efficacy. These results indicate a central role for mTOR in HP-induced CD8+ T cell responses! and demonstrate the importance for CD8+ memory in HP-induced tumor efficacy.
• Th17 Cells Express Interleukin-10 Receptor and Are Controlled by Foxp3− and Foxp3+ Regulatory CD4+ T Cells in an Interleukin-10-Dependent Manner
  - Immunity 34(4):554-565 (2011)
  T helper 17 (Th17) cells are important for host defense against extracellular microorganisms. However, they are also implicated in autoimmune and chronic inflammatory diseases, and as such need to be tightly regulated. The mechanisms that directly control committed pathogenic Th17 cells in vivo remain unclear. We showed here that IL-17A-producing CD4+ T cells expressed interleukin-10 receptor α (IL-10Rα) in vivo. Importantly, T cell-specific blockade of IL-10 signaling led to a selective increase of IL-17A+IFN-γ− (Th17) and IL-17A+IFN-γ+ (Th17+Th1) CD4+ T cells during intestinal inflammation in the small intestine. CD4+Foxp3− IL-10-producing (Tr1) cells and CD4+Foxp3+ regulatory (Treg) cells were able to control Th17 and Th17+Th1 cells in an IL-10-dependent manner in vivo. Lastly, IL-10 treatment of mice with established colitis decreased Th17 and Th17+Th1 cell frequencies via direct signaling in T cells. Thus, IL-10 signaling directly suppresses Th17 and Th17+! Th1 cells.
• Interleukin-10 Signaling in Regulatory T Cells Is Required for Suppression of Th17 Cell-Mediated Inflammation
  - Immunity 34(4):566-578 (2011)
  Effector CD4+ T cell subsets, whose differentiation is facilitated by distinct cytokine cues, amplify the corresponding type of inflammatory response. Regulatory T (Treg) cells integrate environmental cues to suppress particular types of inflammation. In this regard, STAT3, a transcription factor essential for T helper 17 (Th17) cell differentiation, is necessary for Treg cell-mediated control of Th17 cell responses. Here, we showed that anti-inflammatory interleukin-10 (IL-10), and not proinflammatory IL-6 and IL-23 cytokine signaling, endowed Treg cells with the ability to suppress pathogenic Th17 cell responses. Ablation of the IL-10 receptor in Treg cells resulted in selective dysregulation of Th17 cell responses and colitis similar to that observed in mice harboring STAT3-deficient Treg cells. Thus, Treg cells limit Th17 cell inflammation by serving as principal amplifiers of negative regulatory circuits operating in immune effector cells.
• CD94 Is Essential for NK Cell-Mediated Resistance to a Lethal Viral Disease
  - Immunity 34(4):579-589 (2011)
  It is well established that natural killer (NK) cells confer resistance to many viral diseases, but in only a few instances the molecular mechanisms whereby NK cells recognize virus-infected cells are known. Here we show that CD94, a molecule preferentially expressed by NK cells, is essential for the resistance of C57BL/6 mice to mousepox, a disease caused by the Orthopoxvirus ectromelia virus. Ectromelia virus-infected cells expressing the major histocompatibility complex (MHC) class Ib molecule Qa-1b are specifically recognized by the activating receptor formed by CD94 and NKG2E. Because CD94-NKG2 receptors and their ligands are highly conserved in rodents and humans, a similar mechanism may exist during human infections with the smallpox and monkeypox viruses, which are highly homologous to ectromelia virus.
• Bone Marrow Mesenchymal Stem and Progenitor Cells Induce Monocyte Emigration in Response to Circulating Toll-like Receptor Ligands
  - Immunity 34(4):590-601 (2011)
  Inflammatory (Ly6Chi CCR2+) monocytes provide defense against infections but also contribute to autoimmune diseases and atherosclerosis. Monocytes originate from bone marrow and their entry into the bloodstream requires stimulation of CCR2 chemokine receptor by monocyte chemotactic protein-1 (MCP1). How monocyte emigration from bone marrow is triggered by remote infections remains unclear. We demonstrated that low concentrations of Toll-like receptor (TLR) ligands in the bloodstream drive CCR2-dependent emigration of monocytes from bone marrow. Bone marrow mesenchymal stem cells (MSCs) and their progeny, including CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells, rapidly expressed MCP1 in response to circulating TLR ligands or bacterial infection and induced monocyte trafficking into the bloodstream. Targeted deletion of MCP1 from MSCs impaired monocyte emigration from bone marrow. Our findings suggest that bone marrow MSCs and CAR cells respond to circulat! ing microbial molecules and regulate bloodstream monocyte frequencies by secreting MCP1 in proximity to bone marrow vascular sinuses.
• A Subset of Interleukin-21+ Chemokine Receptor CCR9+ T Helper Cells Target Accessory Organs of the Digestive System in Autoimmunity
  - Immunity 34(4):602-615 (2011)
  This study describes a CD4+ T helper (Th) cell subset marked by coexpression of the cytokine interleukin 21 (IL-21) and the gut-homing chemokine receptor CCR9. Although CCR9+ Th cells were observed in healthy mice and humans, they were enriched in the inflamed pancreas and salivary glands of NOD mice and in the circulation of Sjögren's syndrome patients. CCR9+ Th cells expressed large amounts of IL-21, inducible T cell costimulator (ICOS), and the transcription factors Bcl6 and Maf, and also supported antibody production from B cells, thereby resembling T follicular B helper (Tfh) cells. However, in contrast to Tfh cells, CCR9+ Th cells displayed limited expression of CXCR5 and the targets of CCR9+ Th cells were CD8+ T cells whose responsiveness to IL-21 was necessary for the development of diabetes. Thus, CCR9+ Th cells are a subset of IL-21-producing T helper cells that influence regional specification of autoimmune diseases that affect accessory organs of the diges! tive system.
• Allorecognition in a Basal Chordate Consists of Independent Activating and Inhibitory Pathways
  - Immunity 34(4):616-626 (2011)
  Histocompatibility in the basal chordate Botryllus schlosseri is controlled by the polymorphisms of a single gene: the fuhc. A polymorphic candidate receptor (fester) appeared to play roles in both initiating the reaction and discriminating between fuhc alleles. Here we report the characterization of a related protein, uncle fester. uncle fester is not polymorphic, and although coexpressed with fester, has different functional properties. Loss-of-function studies demonstrate that uncle fester was required for incompatible reactions but has no role in interactions between compatible individuals. Furthermore, stimulation with monoclonal antibodies could initiate a rejection phenotype on a single colony, and in both assays the severity of the rejection could be manipulated. These findings suggest that allorecognition in Botryllus consists of independent pathways that control compatible and incompatible outcomes that are integrated within the interacting cells, and may pro! vide insight into basal processes conserved in allorecognition responses throughout the metazoa.
• Structure of a Domain-Swapped FOXP3 Dimer on DNA and Its Function in Regulatory T Cells
  - Immunity 34(4):627 (2011)
  
• An Unexpected Role for Uric Acid as an Inducer of T Helper 2 Cell Immunity to Inhaled Antigens and Inflammatory Mediator of Allergic Asthma
  - Immunity 34(4):627 (2011)