The cytokine transforming growth factor-beta (TGF-beta) converts naïve T cells into regulatory T (Treg) cells that prevent autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-beta has also been found to promote the differentiation of naïve T lymphocytes into proinflammatory IL-17 cytokine-producing T helper 17 (T(H)17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-beta can generate such distinct outcomes. We identified the vitamin A metabolite retinoic acid as a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL-6-driven induction of proinflammatory T(H)17 cells and promoting anti-inflammatory Treg cell differentiation. These findings indicate that a common metabolite can regulate the balance between pro- and anti-inflammatory immunity.

Natural killer T (NKT) cells constitute a highly conserved T lymphocyte subpopulation that has the potential to regulate many types of immune responses through the rapid secretion of cytokines. NKT cells recognize glycolipids presented by CD1d, a class I-like antigen-presenting molecule. They have an invariant T-cell antigen receptor (TCR) alpha-chain, but whether this invariant TCR recognizes microbial antigens is still controversial. Here we show that most mouse and human NKT cells recognize glycosphingolipids from Sphingomonas, Gram-negative bacteria that do not contain lipopolysaccharide. NKT cells are activated in vivo after exposure to these bacterial antigens or bacteria, and mice that lack NKT cells have a marked defect in the clearance of Sphingomonas from the liver. These data suggest that NKT cells are T lymphocytes that provide an innate-type immune response to certain microorganisms through recognition by their antigen receptor, and that they might be useful in providing protection from bacteria that cannot be detected by pattern recognition receptors such as Toll-like receptor 4.

Regulatory T cells (T reg cells) that express the transcription factor Foxp3 suppress the activity of other cells. Here we show that interleukin 10 (IL-10) produced by CD11b + myeloid cells in recombination-activating gene 1-deficient (Rag1 −/− ) recipient mice was needed to prevent the colitis induced by transferred CD4 + CD45RB hi T cells. In Il10 −/− Rag1 −/− mice, T reg cells failed to maintain Foxp3 expression and regulatory activity. The loss of Foxp3 expression occurred only in recipients with colitis, which indicates that the requirement for IL-10 is manifested in the presence of inflammation. IL-10 receptor-deficient (Il10rb −/− ) T reg cells also failed to maintain Foxp3 expression, which suggested that host IL-10 acted directly on the T reg cells. Our data indicate that IL-10 released from myeloid cells acts in a paracrine manner on T reg cells to maintain Foxp3 expression. CD4 + regulatory T cells (T reg cells) express the transcription factor Foxp3 (A002750), which is required for their suppressive function. A T cell-transfer model of colitis has been widely used to study the function of T reg cells in vivo. When CD4 + CD45RB hi T cells are transferred into immunodeficient mice, some of the transferred T cells secrete proinflammatory cytokines and induce an inflammatory bowel disease-like syndrome 1,2 . Cotransfer of sufficient numbers of T reg cells can prevent or even cure this disease 3,4 . The transferred T reg cell populations expand considerably in vivo, and most maintain Foxp3 expression 5,6 .Mice deficient in interleukin 10 (IL-10 (A001243); Il10 −/− mice) or the IL-10 receptor β-chain (IL-10Rβ (A001245); Il10rb −/− mice) develop spontaneous inflammation of the large intestine, a process dominated by a T helper type 1 immune response7 ,8 . Many cell types can produce IL-10, however, and therefore the IL-10 source(s) needed to prevent inflammation must be identified. Much emphasis has been placed on the role of IL-10 released by CD4 + T cells, and in fact mice with conditional deletion of IL-10 in the CD4 + subset develop spontaneous inflammation of the intestine 9 . Mice with deletion of IL-10 solely in Foxp3 + cells also develop inflammation in the intestine and elsewhere, although the pathogenesis is less intense than that in mice completely lacking . Transgenic mice that overexpress IL-10 in intestinal epithelial cells are protected from colitis11, which suggests that IL-10 from nonlymphoid sources can be beneficial, although altered expression in the transgenic mice may not be physiologically relevant. NIH Public AccessTo further elucidate the cellular and molecular basis of the function of IL-10 in regulating colitis, we used the T cell-transfer model described above. We found that IL-10 from nonlymphoid cells, particularly CD11b + CD11c + cells, had an unexpectedly important influence on the development of colitis. Furthermore, we provide evidence that this IL-10 acted in part on T reg cells to maintain their expression of Foxp3, which was otherwise lost in inflammatory condit...

TCRαβ thymocytes differentiate to either CD8αβ cytotoxic T lymphocytes or CD4+ T helper cells. This functional dichotomy is controlled by key transcription factors, including the T helper master regulator, ThPOK, which suppresses the cytolytic program in MHC class II-restricted CD4+ thymocytes. ThPOK continues to repress CD8-lineage genes in mature CD4+ T cells, even as they differentiate to T helper effector subsets. Here we show that the T helper-fate was not fixed and that mature antigen-stimulated CD4+ T cells could terminate Thpok expression and reactivate CD8-lineage genes. This unexpected plasticity resulted in the post-thymic termination of the T helper-program and the functional differentiation of distinct MHC class II-restricted CD4+ cytotoxic T lymphocytes.

The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response1. HVEM was recently reported as a colitis risk locus in patients2, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM3, but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-κB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection4–6, a mouse model for enteropathogenic Escherichia coli infection, Hvem−/− mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 (refs 7 and 8), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection9, HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.

The interaction between the tumor necrosis factor (TNF) family member LIGHT and the TNF family receptor herpes virus entry mediator (HVEM) co-stimulates T cells and promotes inflammation. However, HVEM also triggers inhibitory signals by acting as a ligand that binds to B and T lymphocyte attenuator (BTLA), an immunoglobulin super family member. The contribution of HVEM interacting with these two binding partners in inflammatory processes remains unknown. In this study, we investigated the role of HVEM in the development of colitis induced by the transfer of CD4+CD45RBhigh T cells into recombination activating gene (Rag)−/− mice. Although the absence of HVEM on the donor T cells led to a slight decrease in pathogenesis, surprisingly, the absence of HVEM in the Rag−/− recipients led to the opposite effect, a dramatic acceleration of intestinal inflammation. Furthermore, the critical role of HVEM in preventing colitis acceleration mainly involved HVEM expression by radioresistant cells in the Rag−/− recipients interacting with BTLA. Our experiments emphasize the antiinflammatory role of HVEM and the importance of HVEM expression by innate immune cells in preventing runaway inflammation in the intestine.

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Mammalian target of rapamycin (mTOR) plays a crucial role in the control of T cell fate determination; however, the precise regulatory mechanism of the mTOR pathway is not fully understood. We found that T cell-specific deletion of the gene encoding tuberous sclerosis 1 (TSC1), an upstream negative regulator of mTOR, resulted in augmented Th1 and Th17 differentiation and led to severe intestinal inflammation in a colitis model. Conditional Tsc1 deletion in Tregs impaired their suppressive activity and expression of the Treg marker Foxp3 and resulted in increased IL-17 production under inflammatory conditions. A fate-mapping study revealed that Tsc1-null Tregs that lost Foxp3 expression gained a stronger effector-like phenotype compared with Tsc1 -/-Foxp3 + Tregs. Elevated IL-17 production in Tsc1 -/-Treg cells was reversed by in vivo knockdown of the mTOR target S6K1. Moreover, IL-17 production was enhanced by Treg-specific double deletion of Tsc1 and Foxo3a. Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining immune homeostasis by regulating cell fate determination.