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Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of [CD8.sup.+] T cells in tumor tissue as well as tumortissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not [CD8.sup.+] T cells. Moreover, [TIGIT.sup.+] Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings., Introduction T cell responses are controlled by multiple receptors: while costimulatory receptors ensure optimal T cell activation and proliferation to generate a protective immune response, coinhibitory or checkpoint receptors dampen [...]

[FOXP3.sup.+] Tregs are central for the maintenance of self-tolerance and can be defective In autoimmunity. In multiple sclerosis and type-1 diabetes, dysfunctional self-tolerance is partially mediated by a population of IFNγ-secreting Tregs. It was previously reported that increased NaCl concentrations promote the induction of proinflammatory Th17 cells and that high-salt diets exacerbate experimental models of autoimmunity. Here, we have shown that increasing NaCl, either in vitro or in murine models via diet, markedly impairs Treg function. NaCl increased IFNγ secretion in Tregs, and reducing IFNγ--either by neutralization with anti-IFNγ antibodies or shRNA-mediated knockdown--restored suppressive activity in Tregs. The heightened IFNγ secretion and loss of Treg function were mediated by the serum/glucocorticoid-regulated kinase (SGK1). A high-salt diet also impaired human Treg function and was associated with the induction of IFNγ-secreting Tregs in a xenogeneic graft-versus-host disease model and in adoptive transfer models of experimental colitis. Our results demonstrate a putative role for an environmental factor that promotes autoimmunity by inducing proinflammatory responses in CD4 effector cells and Treg pathways., Introduction Tregs are central in mediating peripheral tolerance and are involved in the maintenance of tolerance to self-antigens (1, 2). Tregs employ Foxp3 as a key transcription factor and are [...]

IL-17-producing [CD4.sup.+] T cells (Th17 cells) have well-described pathogenic roles In tissue Inflammation and autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE); however, the involvement of IL-21 in these processes has remained controversial. While IL-21 is an essential autocrine amplification factor for differentiation of Th17 cells, the loss of IL-21 or IL-21 receptor (IL-21R) does not protect mice from actively induced EAE. Here, we utilized a transgenic EAE mouse model, in which T and B cells overexpress receptors for myelin oligodendrocyte glycoprotein (MOG) (referred to as 2D2xTH mice), and demonstrated that IL-21 is critical for the development of a variant form of spontaneous EAE in these animals. Il21r deletion in 2D2xTH mice reduced the incidence and severity of spontaneous EAE, which was associated with a defect in Th17 cell generation. Moreover, IL-21R deficiency limited IL-23R expression on Th17 cells and inhibited expression of key molecules involved in the generation of pathogenic Th17 cells. Conversely, loss of IL-23R in 2D2xTH mice resulted in complete resistance to the development of spontaneous EAE. Our data identify a previously unappreciated role for IL-21 in EAE and reveal that IL-21-mediated signaling supports generation and stabilization of pathogenic Th17 cells and development of spontaneous autoimmunity., Introduction Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is thought to be driven by pathogenic [CD4.sup.+] Th cells (1, 2). Experimental autoimmune [...]

Cytokines play a critical role in controlling the differentiation of CD4 Th cells into distinct subsets, including IL-17-producing Th17 cells. Unfortunately, the incidence of a number of autoimmune diseases, particularly those in which the IL23/IL-17 axis has been implicated, has risen in the last several decades, suggesting that environmental factors can promote autoimmunity. Here we review the role of cytokines in Th17 differentiation, particularly the role of IL-23 in promoting the differentiation of a pathogenic subset of Th17 cells that potently induce autoimmune tissue inflammation. Moreover, we highlight emerging data that indicate that environmental factors, including the intestinal microbiota and changes in diet, can alter normal cytokine regulation with potent effects on Th17 differentiation and thus promote autoimmunity, which has strong implications for human disease., Introduction The random rearrangement of adaptive antigen receptors allows for incredible diversity of antigen receptor specificity but comes at the cost of creating potentially autoreactive T and B lymphocytes. Although [...]

T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and [...]

Podoplanin (PDPN, also known as Gp38) is highly expressed on the surface of lymphatic endothelial cells, where it regulates development of lymphatic vessels. We have recently observed that PDPN is also expressed on effector T cells that infiltrate target tissues during autoimmune inflammation; however, the function of PDPN in T cells is largely unclear. Here, we demonstrated that global deletion of Pdpn results in exaggerated T cell responses and spontaneous experimental autoimmune encephalomyelitis (EAE) in mice with a susceptible genetic background. In contrast, T cell-specific overexpression of PDPN resulted in profound defects in IL-7-mediated T cell expansion and survival. Consequently, these animals exhibited a more rapid resolution of CNS inflammation, characterized by a reduced effector [CD4.sup.+] T cell population in the CNS. Mice harboring a T cell-specific deletion of Pdpn developed exacerbated EAE, with increased accumulation of effector [CD4.sup.+] T cells in the CNS. Transcriptional profiling of naturally occurring [PDPN.sup.+] effector T cells in the CNS revealed increased expression of other inhibitory receptors, such as Pd1 and Tim3, and decreased expression of prosurvival factors, including Il7ra. Together, our data suggest that PDPN functions as an inhibitory molecule on T cells, thereby promoting tissue tolerance by limiting long-term survival and maintenance of [CD4.sup.+] effector T cells in target organs., Introduction Many autoimmune diseases, including multiple sclerosis (MS), are driven by self-reactive T helper cells that promote autoimmune tissue inflammation, particularly after differentiation into Th1 or Th17 subsets (1). In [...]

Macrophages characterized as M2 and M2-like regulate immune responses associated with immune suppression and healing; however, the relationship of this macrophage subset to [CD169.sup.+] tissue-resident macrophages and their contribution to shaping alloimmune responses is unknown. Here we identified a population of M2-like tissue-resident macrophages that express high levels of the phosphatidylserine receptor TIM-4 and CD169 ([TIM-4.sup.hi[CD169.sup.+]).] Labeling and tracking of [TIM-4.sup.hi][CD169.sup.+] macrophages in mice revealed that this population is a major subset of tissue-resident macrophages, homes to draining LNs following oxidative stress, exhibits an immunoregulatory and hypostimulatory phenotype that is maintained after migration to secondary lymphoid organs, favors preferential induction of antigen-stimulated Tregs, and is highly susceptible to apoptosis. Moreover, [CD169.sup.+] tissue-resident macrophages were resistant to oxidative stress-induced apoptosis in mice lacking TIM-4. Compared with heart allografts from WT mice, [Tim4.sup.-/-] heart allografts survived much longer and were more easily tolerized by non-immunosuppressed recipients. Furthermore, [Tim4.sup.-/-] allograft survival was associated with the infiltration of Tregs into the graft. Together, our data provide evidence that M2-like [TIM-4.sup.hi][CD169.sup.+] tissue-resident macrophages are immunoregulatory and promote engraftment of cardiac allografts, but their influence is diminished by TIM-4-dependent programmed cell death., Introduction Recent advances in macrophage biology have revealed several subpopulations. One prominent categorization separates [Ly6C.sup.+] monocyte-derived macrophages into M1 (destructive, inflammatory) and M2 (healing, immunoregulatory) subsets. Monocytes differentiate into an [...]

Efferocytosis, the process by which dying or dead cells are removed by phagocytosis, has an important role in development, tissue homeostasis and innate immunity (1). Efferocytosis is mediated, in part, by receptors that bind to exofacial phosphatidylserine (PS) on cells or cellular debris after loss of plasma membrane asymmetry. Here we show that abacterial pathogen, Listeria monocytogenes, can exploit efferocytosis to promote cell-to-cell spread during infection. These bacteria can escape the phagosome in host cells by using the poreforming toxin listeriolysin O (LLO) and two phospholipase C enzymes (2). Expression of the cell surface protein ActA allows L. monocytogenes to activate host actin regulatory factors and undergo actin-based motility in the cytosol, eventually leading to formation of actin-rich protrusions at the cell surface. Here we show that protrusion formation is associated with plasma membrane damage due to LLO's poreforming activity. LLO also promotes the release of bacteria-containing protrusions from the host cell, generating membrane-derived vesicles with exofacial PS. The PS-binding receptor TIM-4 (encoded by the Timd4 gene) contributes to efficient cell-to-cell spread by L. monocytogenesin macrophages invitroand growth of these bacteria is impaired in [Timd4.sup.-/-] mice. Thus, L. monocytogenes promotes its dissemination in a host by exploiting efferocytosis. Our results indicate that PS-targeted therapeutics may be useful in the fight against infections by L. monocytogenes and other bacteria that use similar strategies of cell-to-cell spread during infection., The intermediate stages of cell-to-cell spread by L. monocytogenes remain unclear. On the basis of observations with an in vitro infection model, it has been suggested that bacteria-containing protrusions are [...]