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)