CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms. Here, we show that effector-type regulatory T cells (Tregs) are main sCTLA-4 producers in basal and inflammatory states with distinct kinetics upon TCR stimulation. Mice specifically deficient in sCTLA-4 production exhibited spontaneous activation of Th1, Th17, Tfh, and Tc1 cells, autoantibody and IgE production, M1-like macrophage polarization, and impaired wound healing. In contrast, sCTLA-4-intact mCTLA-4-deficient mice, when compared with double-deficient mice, developed milder systemic inflammation and showed predominant activation/differentiation of Th2, M2-like macrophages, and eosinophils. Consistently, recombinant sCTLA-4 inhibited in vitro differentiation of naïve T cells towards Th1 through CD80/CD86 blockade on antigen-presenting cells, but did not affect Th2 differentiation. Moreover, sCTLA-4-intact mCTLA-4-deficient Tregs effectively suppressed Th1-mediated experimental colitis whereas double-deficient Tregs did not. Thus, sCTLA-4 production by Tregs during chronic inflammation is instrumental in controlling type 1 immunity while allowing type 2 immunity to dominate and facilitate inflammation resolution.

CD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell-mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.

Noroviruses can establish chronic infections with active viral shedding in healthy humans but whether persistence is associated with adaptive immune dysfunction is unknown. We used genetically engineered strains of mouse norovirus (MNV) to investigate CD8+ T cell differentiation during chronic infection. We found that chronic infection drove MNV-specific tissue-resident memory (Trm) CD8+ T cells to a differentiation state resembling inflationary effector responses against latent cytomegalovirus with only limited evidence of exhaustion. These MNV-specific Trm cells remained highly functional yet appeared ignorant of ongoing viral replication. Pre-existing MNV-specific Trm cells provided partial protection against chronic infection but largely ceased to detect virus within 72 hours of challenge, demonstrating rapid sequestration of viral replication away from T cells. Our studies revealed a strategy of immune evasion by MNV via the induction of a CD8+ T cell program normally reserved for latent pathogens and persistence in an immune-privileged enteric niche.
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SJL mice represent a mouse model in which young adult females are susceptible to autoimmune disease, while age-matched males are relatively resistant. T cells primed in female SJL mice secrete cytokines associated with a Th1 phenotype. By contrast, T cells primed in males secrete cytokines associated with a Th2 phenotype. Activation of Th2-type T cells in males vs. Th1 cells in females correlates with increased CD4(+)CD25(+) T regulatory cells (Treg) in males. T cells primed in males depleted of CD4(+)CD25(+) T cells preferentially secrete IFN-γ and decreased IL-4 and IL-10 compared to CD4(+)CD25(+) T-cell-sufficient males, suggesting that Treg influence subsequent antigen-specific cytokine secretion. Treg from males and females exhibit equivalent in vitro T-cell suppression. Treg from males express increased CTLA-4 and CD62L and preferentially secrete IL-10. These data suggest that an increased frequency of IL-10 secreting Treg in male SJL mice may contribute resistance to autoimmune disease by favoring the development of Th2 immune responses.

One of the more insidious outcomes of patients who survive severe sepsis is profound immunosuppression. In this study, we addressed the hypothesis that post septic immune defects were due, in part, to the presence and/or expansion of regulatory T cells (Tregs). After recovery from severe sepsis, mice exhibited significantly higher numbers of Tregs, which exerted greater in vitro suppressive activity compared with controls. The expansion of Tregs was not limited to CD25(+) cells, because Foxp3 expression was also detected in CD25(-) cells from post septic mice. This latter group exhibited a significant increase of chromatin remodeling at the Foxp3 promoter, because a marked increase in acetylation at H3K9 was associated with an increase in Foxp3 transcription. Post septic splenic dendritic cells promoted Treg conversion in vitro. Using a solid tumor model to explore the function of Tregs in an in vivo setting, we found post septic mice showed an increase in tumor growth compared with sham-treated mice with a syngeneic tumor model. This observation could mechanistically be related to the ability of post septic Tregs to impair the antitumor response mediated by CD8(+) T cells. Together, these data show that the post septic immune system obstructs tumor immunosurveillance, in part, by augmented Treg expansion and function.