TNF-α has a multifunctional role in autoimmune diseases as reflected in the variable responses of different human diseases to anti–TNF-α therapy. Recent studies have suggested that TNF-α modulates autoimmunity partially via effects on regulatory T cells (Tregs) and that these effects are mediated through the type II TNFR (TNFR2). We have investigated the requirement for TNFR2-expression on murine natural Tregs (nTregs) and induced Tregs (iTregs) in mediating suppression of colitis. Surprisingly, we find that TNFR2-expression is required for both spleen- and thymus-derived nTreg-mediated suppression, but is not required for iTreg-mediated suppression. Abnormal TNFR2−/− nTreg function was not associated with an in vivo decrease in accumulation, stability, or expression of markers known to be relevant in Treg function. Because iTregs are generated in the presence of TGF-β, we investigated whether activation in the presence of TGF-β could overcome the functional defect in TNFR2−/− nTregs. Although preactivation alone did not restore suppressive function of nTregs, preactivation in the presence of TGF-β did. These results identify potentially critical differences in activation requirements for nTregs versus iTregs. Furthermore, our findings are consistent with reports suggesting that nTregs are activated in sites of inflammation while iTregs are activated in lymph nodes. Finally, by demonstrating that nTregs require TNF-α for optimal function whereas iTregs do not, our results suggest that the enigma of variable responses of different human diseases to anti–TNF-α therapy may relate to whether nTregs or iTregs have the predominant regulatory role in a given disease.
Cbl-b is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b−/− mice develop spontaneous autoimmunity, and Cbl-b dysregulation has been described in both murine and human autoimmune diseases. Although the mechanisms underlying the development of autoimmunity in Cbl-b−/− mice are not yet clear, we have reported that Cbl-b−/− CD4+CD25− effector T cells (Teffs) are resistant to CD4+CD25+ regulatory T cell (Treg)-mediated suppression in vitro and have suggested that this may be an important mechanism in the development of autoimmunity. To confirm the relevance of this resistance to autoimmune disease, we now show that Cbl-b−/− Teffs are resistant to suppression by Tregs in vivo and that this involves a resistance of truly naive Cbl-b−/− Teffs. Additionally, we show that Cbl-b−/− Tregs are fully functional in vivo, further suggesting that the regulatory abnormalities in Cbl-b−/− mice are related to defects in Teff, not Treg, function. To characterize the relevance of TGF-β sensitivity in Treg resistance, we examined in vivo Th17 generation and report that Cbl-b−/− mice are able to mount a normal Th17 response in vivo. As Cbl-b−/− Teffs have been shown to be insensitive to the suppressive effects of TGF-β in other in vivo models, the present results suggest that Cbl-b−/− Teffs demonstrate a context-dependent sensitivity to TGF-β in vivo. Overall, our results suggest that resistance to Tregs may be a bona fide mechanism underlying autoimmunity and that Cbl-b−/− mice offer unique approaches for studying the interrelationships between Treg function, TGF-β–mediated responses, and the development of autoimmunity.
The nuclear hormone receptor PPARγ has been shown to play an immuno-regulatory role in many immune-related cell types and activation of PPARγ has been reported to be an effective therapeutic approach in murine and human autoimmune disease. However, despite an association between lymphopenia and autoimmunity, there have been no prior studies of the role of T cell PPARγ in lymphopenia-associated autoimmunity. In the present studies we examined the role of PPARγ in CD4+ T cells in two murine models of lymphopenia-associated autoimmunity. Surprisingly, we find that PPARγ expression in CD4+ CD25− T cells (Teff) is actually required for development of autoimmunity under lymphopenic conditions. Mechanistically, the inability of PPARγ-deficient (T-PPAR) Teff to mediate lymphopenic autoimmunity is associated with a significant decrease in accumulation of Teff in the spleen, lymph nodes and tissues after adoptive transfer. This abnormal accumulation of T-PPAR Teff is associated with defects in both in vivo proliferation and survival. Additionally, T-PPAR Teff demonstrate decreased cytokine production in inflammatory sites and decreased expression of the homing receptor α4β7. Finally, these abnormalities in T-PPAR Teff function were not elicited by lymphopenia alone, but also required the additional activation involved in the mediation of autoimmunity. Thus, in contrast to its documented immunosuppressive role, we now identify an unexpected function for PPARγ in Teff, namely a role in Teff proliferation and survival in lymphopenia-associated autoimmunity. These findings highlight both the multifunctional role of PPARγ in T cells and the complexity of PPARγ as a potential therapeutic target in autoimmunity.
Ligands for the nuclear hormone receptor PPARγ ameliorate many autoimmune conditions in both mice and humans. Recent reports have also suggested that PPARγ is important in regulatory T cell function and in preventing the development of pathogenic Th17 cells. In contrast to this role of PPARγ in suppressing autoimmunity, we now find that CD4+ T cell PPARγ expression is required for development of autoimmunity under lymphopenic conditions. PPARγ-deficient (PPARγ-/-) CD4+ T cells are unable to mediate disease in both murine graft-versus-host disease and an adoptive transfer model of colitis. In the colitis model, PPARγ is required for the accumulation and cytokine production of CD4+ T cells in the spleen, mesenteric lymph nodes, and colonic lamina propria. This defect is specific for CD4+ T cells as PPARγ-/- CD8+ T cells accumulate equally to wild type CD8+ T cells. Mechanistically, PPARγ-/- CD4+ T cells show diminished in vivo proliferation as assessed via Ki67 staining, but no difference in activation marker expression demonstrating that PPARγ is required for proliferation and cytokine production but not for activation. Endogenous PPARγ-/- CD4+ T cells recover normally after mice are sub-lethally irradiated demonstrating that loss of proliferative potential requires antigen-induced activation as well as lymphopenia. Our results identify a novel function for PPARγ in the proliferation and survival of CD4+ T cells in lymphopenia-associated autoimmunity.
TNF-α plays a multifunctional role in autoimmune diseases as reflected in the variable responses of different human diseases to anti-TNF-α therapy. Recent studies have suggested that TNF-α may modulate autoimmunity partially via effects on regulatory T cells (Tregs) mediated through the type II TNF receptor (TNFR2). We have now investigated the requirement for TNFR2 in both murine natural Treg (nTreg) and induced Treg (iTreg) suppression of autoimmunity. Surprisingly, we find that TNFR2 is required for nTreg but not iTreg suppression of colitis. Abnormal TNFR2-/- nTreg function was not associated with a decrease in accumulation, stability or phenotypic markers known to be relevant in Treg function. As iTregs are generated in the presence of TGF-β, we investigated whether activation in the presence of TGF-β could overcome the functional defect in TNFR2-/- nTregs. While pre-activation alone did not restore suppressive function of TNFR2-/- nTregs, pre-activation in the presence of TGF-β did. These results suggest for the first time that nTregs require TNF-α as a critical factor for activation, while iTregs replace this TNF-α requirement with TGF-β. Our findings thus not only expand on previous reports suggesting that nTregs are activated in sites of inflammation while iTregs are activated in lymph nodes, but also lend themselves to a new mechanistic understanding of the enigma of dichotomous responses to anti-TNF-α therapy in human autoimmune diseases.
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