Latest Articles Include:
- Jean Dausset (1916–2009)
- Immunity 31(2):171-173 (2009)
- LAT Polices T Cell Activation
- Immunity 31(2):174-176 (2009)
Mutations in the adaptor molecule LAT can lead to autoimmunity. In this issue of Immunity, Mingueneau et al. (2009) describe how this may not be a failure of central tolerance.
- The Good Fat: A Link between Lipid Bodies and Antigen Cross-presentation
- Immunity 31(2):176-178 (2009)
Antigen cross-presentation enables an efficient CD8+ T cell response against antigens from exogenous sources. In this issue of Immunity, Bougnères et al. (2009) identify lipid bodies as an unexpected new player involved in this complex cellular pathway.
- Blimp Hovers over T Cell Immunity
- Immunity 31(2):178-180 (2009)
The functions of T lymphocytes are regulated by transcription factors controlling gene expression. Three studies in this issue of Immunity ([Kallies et al., 2009], [Rutishauser et al., 2009] and [Shin et al., 2009]) indicate that the transcriptional repressor Blimp-1 promotes the development of short-lived effector cells and regulates clonal exhaustion.
- γδ T Cell Receptors without a Job
- Immunity 31(2):181-183 (2009)
In this issue of Immunity, the studies by Sutton et al. (2009) and Martin et al. (2009) indicate that γδ T cells are innate cells that rapidly produce interleukin (IL)-17 in response to cytokines or pathogens without the need for T cell receptor engagement.
- γδ T Cells and the Lymphoid Stress-Surveillance Response
- Immunity 31(2):184-196 (2009)
The investigation of γδ T cells has identified a rapid lymphoid stress-surveillance response to microbial and nonmicrobial tissue perturbation. In addition to providing local protection, this response provides an immediate source of cytokines, chemokines, and other functions that can substantially affect downstream, adaptive immunity. Recent studies have identified striking mechanisms by which γδ cells meet the requirements of stress surveillance. For example, high response frequencies can reflect a unique nature of antigen engagement by the T cell receptor (TCR), developmental focusing of the repertoire by selection events, or the use of nonclonotypic receptors to initiate responses. Likewise, rapid functional deployment can be facilitated by the preprogramming of γδ cells during development. Additionally, γδ cells can directly influence adaptive immunity by functioning as antigen-presenting cells. With lymphoid stress surveillance likely to underpin numerous ! aspects of inflammation, tumor immunology, infectious disease, and autoimmunity, this perspective considers its properties and its emerging potential for clinical manipulation.
- Loss of the LAT Adaptor Converts Antigen-Responsive T Cells into Pathogenic Effectors that Function Independently of the T Cell Receptor
- Immunity 31(2):197-208 (2009)
Despite compromised T cell antigen receptor (TCR) signaling, mice in which tyrosine 136 of the adaptor linker for activation of T cells (LAT) was constitutively mutated (LatY136F mice) accumulate CD4+ T cells that trigger autoimmunity and inflammation. Here we show that equipping postthymic CD4+ T cells with LATY136F molecules or rendering them deficient in LAT molecules triggers a lymphoproliferative disorder dependent on prior TCR engagement. Therefore, such disorders required neither faulty thymic T cell maturation nor LATY136F molecules. Unexpectedly, in CD4+ T cells recently deprived of LAT, the proximal triggering module of the TCR induced a spectrum of protein tyrosine phosphorylation that largely overlapped the one observed in the presence of LAT. The fact that such LAT-independent signals result in lymphoproliferative disorders with excessive cytokine production demonstrates that LAT constitutes a key negative regulator of the triggering module and of the LAT-! independent branches of the TCR signaling cassette.
- Interleukin-10 Production by Th1 Cells Requires Interleukin-12-Induced STAT4 Transcription Factor and ERK MAP Kinase Activation by High Antigen Dose
- Immunity 31(2):209-219 (2009)
CD4+ T cells producing interleukin-10 (IL-10) and interferon-γ (IFN-γ) are reported in chronic infections. However, the signals that direct the development of IL-10-producing T helper 1 (Th1) cells are undefined. We showed that development of IL-10-producing Th1 cells required high T cell receptor (TCR) ligation, sustained ERK1 and ERK2 MAP kinases phosphorylation, and IL-12-induced STAT4 transcription factor activation. Repeated TCR triggering led to enhanced IL-10 production by Th1 cells, and continued IL-12 action and high-dose TCR signaling were required for the development and maintenance of IL-10-producing Th1 cells. Although Th1, Th2, and Th17 cells require the activation of distinct STATs for their differentiation, activation of ERK1 and ERK2 was a common requirement for production of IL-10 by all Th cell subsets. IL-10 expression also correlated with c-maf expression. Despite having distinct functions in protection against pathogens, all Th cells share the i! mportant task of controlling overexuberant immune responses by means of IL-10 production.
- The Kinase Akt1 Controls Macrophage Response to Lipopolysaccharide by Regulating MicroRNAs
- Immunity 31(2):220-231 (2009)
MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here, we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e and miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4), whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signaling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1−/− macrophages exhibited increased responsiveness to LPS in culture and Akt1−/− mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1−/− macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression.
- A Role for Lipid Bodies in the Cross-presentation of Phagocytosed Antigens by MHC Class I in Dendritic Cells
- Immunity 31(2):232-244 (2009)
Dendritic cells (DCs) have the striking ability to cross-present exogenous antigens in association with major histocompatibility complex (MHC) class I to CD8+ T cells. However, the intracellular pathways underlying cross-presentation remain ill defined. Current models involve cytosolic proteolysis of antigens by the proteasome and peptide import into endoplasmic reticulum (ER) or phagosomal lumen by the transporters associated with antigen processing (TAP1 and TAP2). Here, we show that DCs expressed an ER-resident 47 kDa immune-related GTPase, Igtp (Irgm3). Igtp resides on ER and lipid body (LB) membranes where it binds the LB coat component ADFP. Inactivation of genes encoding for either Igtp or ADFP led to defects in LB formation in DCs and severely impaired cross-presentation of phagocytosed antigens to CD8+ T cells but not antigen presentation to CD4+ T cells. We thus define a new role for LB organelles in regulating cross-presentation of exogenous antigens to CD8+! T lymphocytes in DCs.
- Apoptotic Cells Promote Their Own Clearance and Immune Tolerance through Activation of the Nuclear Receptor LXR
- Immunity 31(2):245-258 (2009)
Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis. The transcriptional pathways that allow macrophages to sense and respond to apoptotic cells are poorly defined. We found that liver X receptor (LXR) signaling was important for both apoptotic cell clearance and the maintenance of immune tolerance. Apoptotic cell engulfment activated LXR and thereby induced the expression of Mer, a receptor tyrosine kinase critical for phagocytosis. LXR-deficient macrophages exhibited a selective defect in phagocytosis of apoptotic cells and an aberrant proinflammatory response to them. As a consequence of these defects, mice lacking LXRs manifested a breakdown in self-tolerance and developed autoantibodies and autoimmune glomerulonephritis. Treatment with an LXR agonist ameliorated disease progression in a mouse model of lupus-like autoimmunity. Thus, activation of LXR by apoptotic cells engages a virtuous cycle that promotes their own clearance ! and couples engulfment to the suppression of inflammatory pathways.
- Guidance of B Cells by the Orphan G Protein-Coupled Receptor EBI2 Shapes Humoral Immune Responses
Gatto D Paus D Basten A Mackay CR Brink R - Immunity 31(2):259-269 (2009)
Humoral immunity depends on both rapid and long-term antibody production against invading pathogens. This is achieved by the generation of spatially distinct extrafollicular plasmablast and follicular germinal center (GC) B cell populations, but the signals that guide responding B cells to these alternative compartments have not been fully elucidated. Here, we show that expression of the orphan G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) by activated B cells was essential for their movement to extrafollicular sites and induction of early plasmablast responses. Conversely, downregulation of EBI2 enabled B cells to access the center of follicles and promoted efficient GC formation. EBI2 therefore provides a previously uncharacterized dimension to B cell migration that is crucial for coordinating rapid versus long-term antibody responses.
- Altered NK Cell Development and Enhanced NK Cell-Mediated Resistance to Mouse Cytomegalovirus in NKG2D-Deficient Mice
Zafirova B Mandarić S Antulov R Krmpotić A Jonsson H Yokoyama WM Jonjić S Polić B - Immunity 31(2):270-282 (2009)
NKG2D is a potent activating receptor on natural killer (NK) cells and acts as a molecular sensor for stressed cells expressing NKG2D ligands such as infected or tumor-transformed cells. Although NKG2D is expressed on NK cell precursors, its role in NK cell development is not known. We have generated NKG2D-deficient mice by targeting the Klrk1 locus. Here we provide evidence for an important regulatory role of NKG2D in the development of NK cells. The absence of NKG2D caused faster division of NK cells, perturbation in size of some NK cell subpopulations, and their augmented sensitivity to apoptosis. As expected, Klrk1−/− NK cells are less responsive to tumor targets expressing NKG2D ligands. Klrk1−/− mice, however, showed an enhanced NK cell-mediated resistance to mouse cytomegalovirus infection as a consequence of NK cell dysregulation. Altogether, these findings provide evidence for regulatory function of NKG2D in NK cell physiology.
- Blimp-1 Transcription Factor Is Required for the Differentiation of Effector CD8+ T Cells and Memory Responses
- Immunity 31(2):283-295 (2009)
In response to viral infection, naive CD8+ T cells proliferate and differentiate into cytotoxic and cytokine-producing effector cells. Here we showed that the transcription factor Blimp-1, a crucial regulator of plasma cell differentiation, was required for CD8+ T cells to differentiate into functional killer T cells in response to influenza virus. Blimp-1 was not essential for the generation of memory T cells but was crucial for their efficient recall response upon reinfection. Antigen-specific Blimp-1-deficient CD8+ T cells failed to appropriately regulate the transcriptional program essential for killer T cell responses and showed impaired migration to the site of infection. This study identifies Blimp-1 as a master regulator of the terminal differentiation of CD8+ effector T cells and uncovers a conservation of the pathways that regulate the terminal differentiation of T and B cells.
- Transcriptional Repressor Blimp-1 Promotes CD8+ T Cell Terminal Differentiation and Represses the Acquisition of Central Memory T Cell Properties
- Immunity 31(2):296-308 (2009)
During acute infections, a small population of effector CD8+ T cells evades terminal differentiation and survives as long-lived memory T cells. We demonstrate that the transcriptional repressor Blimp-1 enhanced the formation of terminally differentiated CD8+ T cells during lymphocytic choriomeningitis virus (LCMV) infection, and Blimp-1 deficiency promoted the acquisition of memory cell properties by effector cells. Blimp-1 expression was preferentially increased in terminally differentiated effector and "effector memory" (Tem) CD8+ T cells, and gradually decayed after infection as central memory (Tcm) cells developed. Blimp-1-deficient effector CD8+ T cells showed some reduction in effector molecule expression, but primarily developed into memory precursor cells that survived better and more rapidly acquired several Tcm cell attributes, including CD62L and IL-2 expression and enhanced proliferative responses. These results reveal a critical role for Blimp-1 in con! trolling terminal differentiation and suppressing memory cell developmental potential in effector CD8+ T cells during viral infection.
- A Role for the Transcriptional Repressor Blimp-1 in CD8+ T Cell Exhaustion during Chronic Viral Infection
- Immunity 31(2):309-320 (2009)
T cell exhaustion is common during chronic infections and can prevent optimal immunity. Although recent studies have demonstrated the importance of inhibitory receptors and other pathways in T cell exhaustion, the underlying transcriptional mechanisms are unknown. Here, we define a role for the transcription factor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Blimp-1 repressed key aspects of normal memory CD8+ T cell differentiation and promoted high expression of inhibitory receptors during chronic infection. These cardinal features of CD8+ T cell exhaustion were corrected by conditionally deleting Blimp-1. Although high expression of Blimp-1 fostered aspects of CD8+ T cell exhaustion, haploinsufficiency indicated that moderate Blimp-1 expression sustained some effector function during chronic viral infection. Thus, we identify Blimp-1 as a transcriptional regulator of CD8+ T cell exhaustion during chronic viral infection and propose that Blimp-1 ! acts as a transcriptional rheostat balancing effector function and T cell exhaustion.
- Interleukin-17-Producing γδ T Cells Selectively Expand in Response to Pathogen Products and Environmental Signals
- Immunity 31(2):321-330 (2009)
γδ T cells are an innate source of interleukin-17 (IL-17), preceding the development of the adaptive T helper 17 (Th17) cell response. Here we show that IL-17-producing T cell receptor γδ (TCRγδ) T cells share characteristic features with Th17 cells, such as expression of chemokine receptor 6 (CCR6), retinoid orphan receptor (RORγt), aryl hydrocarbon receptor (AhR), and IL-23 receptor. AhR expression in γδ T cells was essential for the production of IL-22 but not for optimal IL-17 production. In contrast to Th17 cells, CCR6+IL-17-producing γδ T cells, but not other γδ T cells, express Toll-like receptors TLR1 and TLR2, as well as dectin-1, but not TLR4 and could directly interact with certain pathogens. This process was amplified by IL-23 and resulted in expansion, increased IL-17 production, and recruitment of neutrophils. Thus, innate receptor expression linked with IL-17 production characterizes TCRγδ T cells as an efficient first line of defense that! can orchestrate an inflammatory response to pathogen-derived as well as environmental signals long before Th17 cells have sensed bacterial invasion.
- Interleukin-1 and IL-23 Induce Innate IL-17 Production from γδ T Cells, Amplifying Th17 Responses and Autoimmunity
- Immunity 31(2):331-341 (2009)
Th17 cells, CD4+ T cells that secrete interleukin-17 (IL-17), are pathogenic in autoimmune diseases and their development and expansion is driven by the cytokines IL-6, TGF-β, IL-21, IL-1, and IL-23. However, there are also innate sources of IL-17. Here, we show that γδ T cells express IL-23R and the transcription factor RORγt and produce IL-17, IL-21, and IL-22 in response to IL-1β and IL-23, without T cell receptor engagement. IL-17-producing γδ T cells were found at high frequency in the brain of mice with experimental autoimmune encephalomyelitis (EAE). γδ T cells activated by IL-1β and IL-23 promoted IL-17 production by CD4+ T cells and increased susceptibility to EAE, suggesting that γδ T cells act in an amplification loop for IL-17 production by Th17 cells. Our findings demonstrate that γδ T cells activated by IL-1β and IL-23 are an important source of innate IL-17 and IL-21 and provide an alternative mechanism whereby IL-1 and IL-23 may mediate a! utoimmune inflammation.
- Dynamics of T Cell, Antigen-Presenting Cell, and Pathogen Interactions during Recall Responses in the Lymph Node
- Immunity 31(2):342-355 (2009)
Memory T cells circulate through lymph nodes where they are poised to respond rapidly upon re-exposure to a pathogen; however, the dynamics of memory T cell, antigen-presenting cell, and pathogen interactions during recall responses are largely unknown. We used a mouse model of infection with the intracellular protozoan parasite, Toxoplasma gondii, in conjunction with two-photon microscopy, to address this question. After challenge, memory T cells migrated more rapidly than naive T cells, relocalized toward the subcapsular sinus (SCS) near invaded macrophages, and engaged in prolonged interactions with infected cells. Parasite invasion of T cells occurred by direct transfer of the parasite from the target cell into the T cell and corresponded to an antigen-specific increase in the rate of T cell invasion. Our results provide insight into cellular interactions during recall responses and suggest a mechanism of pathogen subversion of the immune response.
- Notch and Wingless Signaling Cooperate in Regulation of Dendritic Cell Differentiation
- Immunity 31(2):356 (2009)