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• W2019916645 abstract "Is transforming growth factor-β (TGF-β) required for induction of the transcription factor Foxp3 in developing thymocytes? Ouyang et al., 2010Ouyang W. Beckett O. Ma Q. Li M.O. Immunity. 2010; 32 (this issue): 642-653Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar demonstrate that TGF-β in the thymus prevents deletion of Foxp3+ regulatory T cells. Is transforming growth factor-β (TGF-β) required for induction of the transcription factor Foxp3 in developing thymocytes? Ouyang et al., 2010Ouyang W. Beckett O. Ma Q. Li M.O. Immunity. 2010; 32 (this issue): 642-653Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar demonstrate that TGF-β in the thymus prevents deletion of Foxp3+ regulatory T cells. Transforming growth factor-β (TGF-β) is a regulatory cytokine that has pleiotropic effects on many different cells types (Li and Flavell, 2008Li M.O. Flavell R.A. Cell. 2008; 134: 392-404Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar). Although TGF-β exists in three isoforms, TGF-β1 is the predominant form expressed in the immune system. Active TGF-β signals by binding simultaneously to two transmembrane serine-threonine kinase receptors, TGF-β receptor I (TGF-βRI) and TGF-β receptor II (TGF-βRII). TGF-β elicits diverse cellular responses that are primarily mediated through the actions of the Smad family of transcription factors, but TGF-β can also signal via Smad-independent pathways. The phenotype of TGF-β1-, TGF-βRI-, and TGF-βRII-deficient animals closely resembles that of animals deficient in the transcription factor Foxp3 that lack regulatory T (Treg) cells, and all mutant strains develop a lethal autoimmune syndrome and die at 3–4 weeks of age. Given that TGF-β plays a critical role in the induction of Foxp3+ T cells in vitro and in extrathymic sites in vivo, these studies have raised the possibility that TGF-β may play a role in the induction of Foxp3+ T cells during thymic development. Although this question might be easily addressed by analysis of Treg cell populations in TGF-β1-deficient mice, these mice have relatively normal numbers of Treg cells in the thymus before inflammation develops (Marie et al., 2005Marie J.C. Letterio J.J. Gaving M. Rudensky A.Y. J. Exp. Med. 2005; 201: 1061-1067Crossref PubMed Scopus (792) Google Scholar), given that they receive maternal TGF-β protein from their mother's milk. A potential role for TGF-β in the induction of the development of Foxp3+ Treg cells in the thymus of TGF-βRI-deficient mice has been described (Liu et al., 2008Liu Y. Zhang P. Li J. Kulkarni A.B. Perruche P. Chen W. Nat. Immunol. 2008; 9: 632-640Crossref PubMed Scopus (415) Google Scholar). In this issue of Immunity, Ouyang et al., 2010Ouyang W. Beckett O. Ma Q. Li M.O. Immunity. 2010; 32 (this issue): 642-653Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar use TGF-βRII-deficient mice and present an alternative model by demonstrating that TGF-β is critical for the development of Foxp3+ T cells in the thymus by preventing Bim-dependent apoptosis rather than by inducing Foxp3 expression. Very few CD4+Foxp3+ cells could be detected in the thymus of the TGF-βRI-deficient mice between 3 and 5 days of age, whereas the number of CD4+Foxp3− T cells appeared to be normal (Liu et al., 2008Liu Y. Zhang P. Li J. Kulkarni A.B. Perruche P. Chen W. Nat. Immunol. 2008; 9: 632-640Crossref PubMed Scopus (415) Google Scholar). Surprisingly, intrathymic Foxp3+ T cells expanded beginning at 7 days of age, and at 3–4 weeks of age, the number of Foxp3+ cell in the thymus was higher than normal. Most importantly, thymocytes from the TGF-βRI-deficient mice had enhanced interleukin-2 (IL-2) production and it seemed likely that IL-2 was driving the proliferation of the few CD4+25+Foxp3+ cells that developed in the absence of TGF-β signaling. The role of IL-2 in the expansion of the Foxp3+ T cells was conclusively demonstrated by breeding the TGF-βRI deficient mice to IL-2-deficient mice. Whereas deletion of IL-2 alone resulted in slightly fewer Foxp3+ thymocytes, the doubly deficient mice completely lacked Foxp3+ thymocytes at 3–4 weeks of age. In addition, there was a complete absence of Foxp3+ Treg cells in spleen and the mice rapidly succumbed to autoimmune inflammation. Although the authors concluded that TGF-β signaling is required for the development of Foxp3+ Treg cells in the thymus, it remains unclear at what stage and in which thymocyte population TGF-β mediated this process. Normal to increased numbers of Foxp3+ T cells in the thymus of 2- to 3-week-old TGF-βRII-deficient mice were also observed (Li et al., 2006Li M.O. Sanjabi S. Flavell R.A. Immunity. 2006; 25: 455-471Abstract Full Text Full Text PDF PubMed Scopus (596) Google Scholar), but earlier time points were not examined. However, a decrease in the percentage of Treg cells among peripheral CD4+ T cells was observed, and this was interpreted as being secondary to the requirement for TGF-β for peripheral Treg cell survival (Marie et al., 2005Marie J.C. Letterio J.J. Gaving M. Rudensky A.Y. J. Exp. Med. 2005; 201: 1061-1067Crossref PubMed Scopus (792) Google Scholar). In the present study, Ouyang et al., 2010Ouyang W. Beckett O. Ma Q. Li M.O. Immunity. 2010; 32 (this issue): 642-653Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar have re-explored in depth the role of TGF-β in controlling the survival of both conventional T cells and Treg cells during thymic negative selection and development. They bred the TGF-βRII-deficient mice to mice expressing the OT-II TCR transgene on a RAG-deficient background. Blockade of TGF-β signaling in OT-II cells resulted in their heightened deletion in the thymus. Similarly, increased apoptosis was observed in TCR-βhi T cells from the TGF-βRII-deficient mice when thymocytes were stimulated with anti-CD3 in vitro. TGF-β also controlled peripheral T cell tolerance to a “neo-self” antigen, ovalbumin. Although wild-type OT-II mice expressing a transgene encoding membrane ovalbumin did not develop diabetes, the same mice lacking TGF-βRII developed severe diabetes between 6 and 10 weeks of age. Even though these mice demonstrated enhanced thymic negative selection of conventional T cells in the absence of TGF-β signaling, an intact TGF-β signaling pathway was also essential for the maintenance of tolerance in the periphery. As was observed in the TGF-βRI-deficient mice (Liu et al., 2008Liu Y. Zhang P. Li J. Kulkarni A.B. Perruche P. Chen W. Nat. Immunol. 2008; 9: 632-640Crossref PubMed Scopus (415) Google Scholar), the number of Foxp3+ thymocytes was reduced by 80% in 3- to 5-day-old TGF-βRII-deficient mice. Notably, Foxp3+ T cells in the TGF-βRII mice expressed high amounts of caspase, as well as higher numbers of cells expressing the proliferation marker Ki-67, and manifested a 5-fold increase in cell death when cultured for 12 hr in vitro. The major mechanistic advance in these studies was the demonstration that enhanced apoptosis of TGFβ-RII-deficient Treg cells was associated with high amounts of the proapoptotic Bcl-2 family members Bim, Bak, and Bax (Figure 1). Bim deficiency restored peripheral Treg cells, inhibited T cell activation, and enhanced the lifespan of deficient mice, but could not prevent the development of lethal inflammation. Bim ablation did not completely rescue caspase activation in TGF-βRII-deficient mice, raising the possibility that other Bcl-2 family proteins might control Bim-independent caspase activation. The authors conclude that TGF-β signaling is not required for Foxp3+ Treg cell development, but rather that the antiapoptotic effects of TGF-β are required for Treg cell survival. Although many studies have focused on the negative effects of TGF-β on immune responses, the demonstration that TGF-β exerts positive long-term growth promoting effects on T cells as well as protection from apoptosis has been known for almost 20 years (reviewed in Golstein and Wyllie, 2001Golstein P. Wyllie A.H. J. Exp. Med. 2001; 194: F19-F21Crossref PubMed Google Scholar). For example, TGF-β increased proliferation and IFN-γ production in CD8+ T cells, and TGF-β and IL-2 were shown to synergize in the prevention of apoptotic death of Th2 cell effectors leading to prolonged expansion of the effector populations. TGF-β has been shown to modulate activation induced T cell death by inhibiting the induction of FasL mRNA. One of the most convincing studies of the antiapoptotic function of TGF-β was the demonstration of an increase in apoptosis in TGF-β-deficient thymocytes that occurred before overt signs of inflammation and immunopathology developed and was evident even in day 18 fetal thymocytes (Chen et al., 2001Chen W. Jin W. Tian H. Sicurello P. Frank M. Orenstein J.M. Wahl S.M. J. Exp. Med. 2001; 194: 439-455Crossref PubMed Scopus (103) Google Scholar). Surprisingly, exogenous TGF-β failed to rescue spontaneous and death-receptor-mediated T cell apoptosis in TGF-β-deficient T cells, and enhancement of spontaneous or TCR-induced death was not observed in T cells deficient in Smad3. One possible explanation for these results was that TGF-β was acting intracellularly and exerting its antiapoptotic effects by maintaining the integrity of mitochondrial membranes. Although this study did not examine apoptosis of Foxp3+ T cells in the thymus, the results are quite compatible with all of the observations of Ouyang et al., 2010Ouyang W. Beckett O. Ma Q. Li M.O. Immunity. 2010; 32 (this issue): 642-653Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar and support the conclusion that the decreased number of Foxp3+ Treg cells early in life in the receptor-deficient mice is secondary to enhanced apoptosis. Collectively, these studies strongly support the view that TGF-β is not essential for the induction of Foxp3 expression during Treg cell development in the thymus. It is clear in both studies (Liu et al., 2008Liu Y. Zhang P. Li J. Kulkarni A.B. Perruche P. Chen W. Nat. Immunol. 2008; 9: 632-640Crossref PubMed Scopus (415) Google Scholar, Ouyang et al., 2010Ouyang W. Beckett O. Ma Q. Li M.O. Immunity. 2010; 32 (this issue): 642-653Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar) that low numbers of Foxp3+ thymocytes can be detected at day 3–4 of life in the TGF-β receptor-deficient strains. The factors that are required for the generation of these cells remain unknown. The studies from the Li laboratory (Ouyang et al., 2010Ouyang W. Beckett O. Ma Q. Li M.O. Immunity. 2010; 32 (this issue): 642-653Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar) demonstrate that the low numbers of Foxp3+ T cells detected at day 3–4 of life are secondary to enhanced Bcl-2 family-mediated apoptosis, but the few surviving cells are highly activated and proliferating. Why then are relatively normal numbers of Foxp3+ T cell observed at 2–4 weeks of age? It is likely that IL-2 is responsible for the expansion of the Foxp3+ T cells to near normal numbers on day 14 of life (Liu et al., 2008Liu Y. Zhang P. Li J. Kulkarni A.B. Perruche P. Chen W. Nat. Immunol. 2008; 9: 632-640Crossref PubMed Scopus (415) Google Scholar). In many respects, the more important take-home lesson from this series of papers (Chen et al., 2001Chen W. Jin W. Tian H. Sicurello P. Frank M. Orenstein J.M. Wahl S.M. J. Exp. Med. 2001; 194: 439-455Crossref PubMed Scopus (103) Google Scholar, Liu et al., 2008Liu Y. Zhang P. Li J. Kulkarni A.B. Perruche P. Chen W. Nat. Immunol. 2008; 9: 632-640Crossref PubMed Scopus (415) Google Scholar, Li and Flavell, 2008Li M.O. Flavell R.A. Cell. 2008; 134: 392-404Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, Ouyang et al., 2010Ouyang W. Beckett O. Ma Q. Li M.O. Immunity. 2010; 32 (this issue): 642-653Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar) is the equally critical role of TGF-β in the development of conventional T cells by enhancing cell survival. Furthermore, it remains unclear how the TGF-β-mediated survival signals control and maintain the balance between the development of conventional T cells and Treg cells. Lastly, the cell type(s) responsible for the production of TGF-β in the thymus remain unknown. Although almost all cells can produce TGF-β, one intriguing possibility is that thymic Foxp3+ cells themselves are a major source. It has recently been shown (Tran et al., 2009Tran D.Q. Andersson J. Wang R. Ramsey H. Unutmaz D. Shevach E.M. Proc. Natl. Acad. Sci. USA. 2009; 106: 13445-13450Crossref PubMed Scopus (311) Google Scholar) that activated Foxp3+ T cells express latent TGF-β bound to their surface via a leucine-rich repeat protein termed GARP. Thus, Treg cells functioning in a positive feedback loop could provide the TGF-β needed for their own survival as well as the survival of conventional T cells. Transforming Growth Factor-β Signaling Curbs Thymic Negative Selection Promoting Regulatory T Cell DevelopmentOuyang et al.ImmunityMay 13, 2010In BriefThymus-derived naturally occurring regulatory T (nTreg) cells are necessary for immunological self-tolerance. nTreg cell development is instructed by the T cell receptor and can be induced by agonist antigens that trigger T cell-negative selection. How T cell deletion is regulated so that nTreg cells are generated is unclear. Here we showed that transforming growth factor-β (TGF-β) signaling protected nTreg cells and antigen-stimulated conventional T cells from apoptosis. Enhanced apoptosis of TGF-β receptor-deficient nTreg cells was associated with high expression of proapoptotic proteins Bim, Bax, and Bak and low expression of the antiapoptotic protein Bcl-2. Full-Text PDF Open Archive" @default.
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• W2019916645 date "2010-05-01" @default.
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• W2019916645 title "TGF-β to the Rescue" @default.
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