Hot off the presses! Mar 25 Immunity

The Mar 25 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:

• The Immutable Recognition of CD1d
  - Immunity 34(3):281-283 (2011)
  CD1d presents lipid antigens to natural killer T cells. In this issue of Immunity, Wun et al. (2011) and Mallevaey et al. (2011) explore the molecular details of nonself lipid discrimination and self-recognition.
• Caspase-8: Clipping off RIG-I Signaling
  - Immunity 34(3):283-285 (2011)
  Activation of the RIG-I signaling molecule is essential for antiviral immunity but mechanisms downmodulating the response are ill defined. In this issue of Immunity, Rajput et al. (2011) describe caspase-8-mediated RIP1 cleavage as a key step for restricting RIG-I signaling.
• Viperin Links Lipid Bodies to Immune Defense
  - Immunity 34(3):285-287 (2011)
  Viperin is an interferon-stimulated gene that exerts antiviral effects. In this issue of Immunity, Saitoh et al. (2011) uncovered an unexpected function of Viperin and lipid bodies in interferon induction by Toll-like receptors, specifically in plasmacytoid dendritic cells.
• TGF-β in Th17 Cell Development: The Truth Is Out There
  - Immunity 34(3):288-290 (2011)
  As Th17 cell developmental requirements continue to be studied, Gutcher et al. (2011) demonstrate in this issue of Immunity that autocrine TGF-β cytokine promotes Th17 cell development and maintenance.
• Eat Your Carrots! T Cells Are RARing to Go
  - Immunity 34(3):290-292 (2011)
  In this issue of Immunity, Hall et al. (2011) show that vitamin A and its metabolites play a central role in regulating adaptive immunity by promoting the development of both inflammatory and regulatory T cell responses.
• Experimental Inflammatory Bowel Disease: Insights into the Host-Microbiota Dialog
  - Immunity 34(3):293-302 (2011)
  Inflammatory bowel disease appears to result from an abnormal host immune response to the intestinal microbiota. Experimental models have allowed the dissection of the complex dialog between the host and its microbiota. Through genetic manipulation of the host genome the immune compartments, cells, molecules, and genes that are critical for maintenance of intestinal homeostasis are being identified. Genetic association studies in humans have identified over 100 susceptibility loci. Although there is remarkable coherence between the experimental model and the human genetic data, a full understanding of the mechanisms involved in genetic susceptibility to IBD and of gene-gene and gene-environmental interactions will require a "next generation" of experimental models.
• RUNX Transcription Factor-Mediated Association of Cd4 and Cd8 Enables Coordinate Gene Regulation
  - Immunity 34(3):303-314 (2011)
  T cell fate is associated with mutually exclusive expression of CD4 or CD8 in helper and cytotoxic T cells, respectively. How expression of one locus is temporally coordinated with repression of the other has been a long-standing enigma, though we know RUNX transcription factors activate the Cd8 locus, silence the Cd4 locus, and repress the Zbtb7b locus (encoding the transcription factor ThPOK), which is required for CD4 expression. Here we found that nuclear organization was altered by interplay among members of this transcription factor circuitry: RUNX binding mediated association of Cd4 and Cd8 whereas ThPOK binding kept the loci apart. Moreover, targeted deletions within Cd4 modulated CD8 expression and pericentromeric repositioning of Cd8. Communication between Cd4 and Cd8 thus appears to enable long-range epigenetic regulation to ensure that expression of one excludes the other in mature CD4 or CD8 single-positive (SP) cells.
• A Molecular Basis for NKT Cell Recognition of CD1d-Self-Antigen
  - Immunity 34(3):315-326 (2011)
  The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 Å resolution structure of an autoreactive NKT TCR-phosphatidylinositol-CD1d complex. NKT TCR recognition of self- and foreign antigens was underpinned by a similar mode of germline-encoded recognition of CD1d. However, NKT TCR autoreactivity is mediated by unique sequences within the non-germline-encoded CDR3β loop encoding for a hydrophobic motif that promotes self-association with CD1d. Accordingly, NKT cell autoreactivity may arise from the inherent affinity of the interaction between CD1d and the NKT TCR, resulting in the recognition of a broad range of CD1d-restricted self-antigens. This demonstrates that multiple self-antigens can be recognized in a similar man! ner by autoreactive NKT TCRs.
• A Molecular Basis for the Exquisite CD1d-Restricted Antigen Specificity and Functional Responses of Natural Killer T Cells
  - Immunity 34(3):327-339 (2011)
  Natural killer T (NKT) cells respond to a variety of CD1d-restricted antigens (Ags), although the basis for Ag discrimination by the NKT cell receptor (TCR) is unclear. Here we have described NKT TCR fine specificity against several closely related Ags, termed altered glycolipid ligands (AGLs), which differentially stimulate NKT cells. The structures of five ternary complexes all revealed similar docking. Acyl chain modifications did not affect the interaction, but reduced NKT cell proliferation, indicating an affect on Ag processing or presentation. Conversely, truncation of the phytosphingosine chain caused an induced fit mode of TCR binding that affected TCR affinity. Modifications in the glycosyl head group had a direct impact on the TCR interaction and associated cellular response, with ligand potency reflecting the t1/2 life of the interaction. Accordingly, we have provided a molecular basis for understanding how modifications in AGLs can result in striking alter! ations in the cellular response of NKT cells.
• RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein
  - Immunity 34(3):340-351 (2011)
  Excessive responses to pattern-recognition receptors are prevented by regulatory mechanisms that affect the amounts and activities of the downstream signaling proteins. We report that activation of the transcription factor IRF3 by the ribonucleic acid sensor RIG-I was restricted by caspase-8-mediated cleavage of the RIP1 protein, which resulted in conversion of RIP1 from a signaling enhancer to a signaling inhibitor. The proteins RIP1 and caspase-8 were recruited to the RIG-I complex after viral infection and served antagonistic regulatory roles. Conjugation of ubiquitin chains to RIP1 facilitated assembly of the RIG-I complex, resulting in enhanced phosphorylation of IRF3. However, the ubiquitination of RIP1 also rendered it susceptible to caspase-8-mediated cleavage that yielded an inhibitory RIP1 fragment. The dependence of RIP1 cleavage on the same molecular change as that facilitating RIG-I signaling allows for RIG-I signaling to be restricted in its duration with! out compromising its initial activation.
• Antiviral Protein Viperin Promotes Toll-like Receptor 7- and Toll-like Receptor 9-Mediated Type I Interferon Production in Plasmacytoid Dendritic Cells
  - Immunity 34(3):352-363 (2011)
  Toll-like receptor 7 (TLR7) and TLR9 sense viral nucleic acids and induce production of type I interferon (IFN) by plasmacytoid dendritic cells (pDCs) to protect the host from virus infection. We showed that the IFN-inducible antiviral protein Viperin promoted TLR7- and TLR9-mediated production of type I IFN by pDCs. Viperin expression was potently induced after TLR7 or TLR9 stimulation and Viperin localized to the cytoplasmic lipid-enriched compartments, lipid bodies, in pDCs. Viperin interacted with the signal mediators IRAK1 and TRAF6 to recruit them to the lipid bodies and facilitated K63-linked ubiquitination of IRAK1 to induce the nuclear translocation of transcription factor IRF7. Loss of Viperin reduced TLR7- and TLR9-mediated production of type I IFN by pDCs. However, Viperin was dispensable for the production of type I IFN induced by intracellular nucleic acids. Thus, Viperin mediates its antiviral function via the regulation of the TLR7 and TLR9-IRAK1 signal! ing axis in pDCs.
• RelA and RelB Transcription Factors in Distinct Thymocyte Populations Control Lymphotoxin-Dependent Interleukin-17 Production in γδ T Cells
  - Immunity 34(3):364-374 (2011)
  The NF-κB transcription factor regulates numerous immune responses but its contribution to interleukin-17 (IL-17) production by T cells is largely unknown. Here, we report that IL-17, but not interferon-γ (IFN-γ), production by γδ T cells required the NF-κB family members RelA and RelB as well as the lymphotoxin-β-receptor (LTβR). In contrast, LTβR-NF-κB signaling was not involved in the differentiation of conventional αβ Th17 cells. Impaired IL-17 production in RelA- or RelB-deficient T cells resulted in a diminished innate immune response to Escherichia coli infection. RelA controlled the expression of LT ligands in accessory thymocytes whereas RelB, acting downstream of LTβR, was required for the expression of RORγt and RORα4 transcription factors and the differentiation of thymic precursors into γδT17 cells. Thus, RelA and RelB within different thymocyte subpopulations cooperate in the regulation of IL-17 production by γδ T cells and contribute t! o the host's ability to fight bacterial infections.
• Selective Utilization of Toll-like Receptor and MyD88 Signaling in B Cells for Enhancement of the Antiviral Germinal Center Response
  - Immunity 34(3):375-384 (2011)
  The contribution of Toll-like receptor (TLR) signaling to T cell-dependent (TD) antibody responses was assessed by using mice lacking the TLR signaling adaptor MyD88 in individual cell types. When a soluble TLR9 ligand was used as adjuvant for a protein antigen, MyD88 was required in dendritic cells but not in B cells to enhance the TD antibody response, regardless of the inherent immunogenicity of the antigen. In contrast, a TLR9 ligand contained within a virus-like particle substantially augmented the TD germinal center IgG antibody response, and this augmentation required B cell MyD88. The ability of B cells to discriminate between antigens based on the physical form of a TLR ligand probably reflects an adaptation to facilitate strong antiviral antibody responses.
• Paired Immunoglobin-like Receptor-B Regulates the Suppressive Function and Fate of Myeloid-Derived Suppressor Cells
  - Immunity 34(3):385-395 (2011)
  Myeloid-derived suppressor cells (MDSCs) bear characteristics of precursors for both M1 and M2 macrophages. The molecular mechanism underlying the differentiation into M1 and M2 macrophages and the relationship of this differentiation to antitumor responses remains largely undefined. Herein, we investigate the potential function of paired immunoglobulin-like receptor B (PIR-B), also known as leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3) in MDSC differentiation, and its role in tumor-induced immunity. Our studies indicated that MDSCs genetically ablated for PIR-B (Lilrb3−/−) underwent a specific transition to M1-like cells when entering the periphery from bone marrow, resulting in decreased suppressive function, regulatory T cell activation activity, primary tumor growth, and lung metastases. Activation of Toll-like receptor (TLR), signal transducers, and activators of transcription 1 (STAT1), and nuclear factor-kappa B (NF-κB) signaling in L! ilrb3−/− MDSC promoted the acquisition of M1 phenotype. Inhibition of the PIR-B signaling pathway promoted MDSC differentiation into M1 macrophages.
• Autocrine Transforming Growth Factor-β1 Promotes In Vivo Th17 Cell Differentiation
  - Immunity 34(3):396-408 (2011)
  TGF-β1 is a regulatory cytokine that has an important role in controlling T cell differentiation. T cell-produced TGF-β1 acts on T cells to promote Th17 cell differentiation and the development of experimental autoimmune encephalomyelitis (EAE). However, the exact TGF-β1-producing T cell subset required for Th17 cell generation and its cellular mechanism of action remain unknown. Here we showed that deletion of the Tgfb1 gene from activated T cells and Treg cells, but not Treg cells alone, abrogated Th17 cell differentiation, resulting in almost complete protection from EAE. Furthermore, differentiation of T cells both in vitro and in vivo demonstrated that TGF-β1 was highly expressed by Th17 cells and acted in a predominantly autocrine manner to maintain Th17 cells in vivo. These findings reveal an essential role for activated T cell-produced TGF-β1 in promoting the differentiation of Th17 cells and controlling inflammatory diseases.
• Foxp3+ Regulatory T Cells Promote T Helper 17 Cell Development In Vivo through Regulation of Interleukin-2
  - Immunity 34(3):409-421 (2011)
  T helper 17 (Th17) cell development is driven by cytokines including transforming growth factor-β (TGF-β), interleukin-6 (IL-6), IL-1, and IL-23. Regulatory T (Treg) cells can provide the TGF-β in vitro, but their role in vivo remains unclear, particularly because Treg cells inhibit inflammation in many models of Th17 cell-associated autoimmunity. We used mice expressing Diphtheria toxin receptor under control of the Foxp3 promoter to deplete Foxp3+ Treg cells in adult mice during in vivo Th17 cell priming. Treg cell depletion resulted in a reduced frequency of antigen-specific IL-17 producers in draining lymph nodes and blood, correlating with reduced inflammatory skin responses. In contrast, Treg cells did not promote IL-17 secretion after initial activation stages. Treg cell production of TGF-β was not required for Th17 cell promotion, and neither was suppression of Th1 cell-associated cytokines. Rather, regulation of IL-2 availability and resultant signaling th! rough CD25 by Treg cells was found to play an important role.
• CD4+CD25+Foxp3+ Regulatory T Cells Promote Th17 Cells In Vitro and Enhance Host Resistance in Mouse Candida albicans Th17 Cell Infection Model
  - Immunity 34(3):422-434 (2011)
  Th17 cells and CD4+CD25+Foxp3+ regulatory T (Treg) cells are thought to promote and suppress inflammatory responses, respectively. Here we explore why under Th17 cell polarizing conditions, Treg cells did not suppress, but rather upregulated, the expression of interleukin-17A (IL-17A), IL-17F, and IL-22 from responding CD4+ T cells (Tresp cells). Upregulation of IL-17 cytokines in Tresp cells was dependent on consumption of IL-2 by Treg cells, especially at early time points both in vitro and in vivo. During an oral Candida albicans infection in mice, Treg cells induced IL-17 cytokines in Tresp cells, which markedly enhanced fungal clearance and recovery from infection. These findings show how Treg cells can promote acute Th17 cell responses to suppress mucosal fungus infections and reveal that Treg cells have a powerful capability to fight infections besides their role in maintaining tolerance or immune homeostasis.
• Essential Role for Retinoic Acid in the Promotion of CD4+ T Cell Effector Responses via Retinoic Acid Receptor Alpha
  - Immunity 34(3):435-447 (2011)
  Vitamin A and its metabolite, retinoic acid (RA) are implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells. Here we showed RA was also required to elicit proinflammatory CD4+ helper T cell responses to infection and mucosal vaccination. Retinoic acid receptor alpha (RARα) was the critical mediator of these effects. Antagonism of RAR signaling and deficiency in RARα (Rara−/−) resulted in a cell-autonomous CD4+ T cell activation defect, which impaired intermediate signaling events, including calcium mobilization. Altogether, these findings reveal a fundamental role for the RA-RARα axis in the development of both regulatory and inflammatory arms of adaptive immunity and establish nutritional status as a broad regulator of adaptive T cell responses.
• Interleukin-23 Drives Intestinal Inflammation through Direct Activity on T Cells
  - Immunity 34(3):448 (2011)
  
• Nuclear Export of the NF-κB Inhibitor IκBα Is Required for Proper B Cell and Secondary Lymphoid Tissue Formation
  - Immunity 34(3):449 (2011)