Treg Cells Acquire New Directions, Cytokines Navigate
2012; Cell Press; Volume: 37; Issue: 3 Linguagem: Inglês
10.1016/j.immuni.2012.09.004
ISSN1097-4180
AutoresNaganari Ohkura, Shimon Sakaguchi,
Tópico(s)Immunotherapy and Immune Responses
ResumoFoxp3+ Treg cells express transcription factors normally expressed by specific T helper cells at sites of inflammation. In this issue of Immunity, Koch et al., 2012Koch M.A. Thomas K.N. Perdue N.R. Smigiel K.S. Srivastava S. Campbell D.J. Immunity. 2012; 37 (this issue): 501-510Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar and Hall et al., 2012Hall A.O. Beiting D.P. Tato C. John B. Oldenhove G. Gonzalez Lombana C. Harms Pritchard G. Silver J.S. Bouladoux N. Stumhofer J.S. et al.Immunity. 2012; 37 (this issue): 511-523Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar demonstrate that IFN-γ and IL-27 distinctly induces T-bet+ Treg cells via STAT-1 transcription factor activation. Foxp3+ Treg cells express transcription factors normally expressed by specific T helper cells at sites of inflammation. In this issue of Immunity, Koch et al., 2012Koch M.A. Thomas K.N. Perdue N.R. Smigiel K.S. Srivastava S. Campbell D.J. Immunity. 2012; 37 (this issue): 501-510Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar and Hall et al., 2012Hall A.O. Beiting D.P. Tato C. John B. Oldenhove G. Gonzalez Lombana C. Harms Pritchard G. Silver J.S. Bouladoux N. Stumhofer J.S. et al.Immunity. 2012; 37 (this issue): 511-523Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar demonstrate that IFN-γ and IL-27 distinctly induces T-bet+ Treg cells via STAT-1 transcription factor activation. CD4+ T cells are important for host defense in their role as specialized T helper (Th) cell subsets (e.g., Th1, Th2, Th17, and Tfh), which express specific transcription factors, such as T-bet, Gata3, IRF4, RORγt, and BCL-6. Foxp3+ regulatory T (Treg) cells, in contrast, are indispensable for the maintenance of immune tolerance and homeostasis via mainly controlling the development and expansion of these Th cell populations (Sakaguchi et al., 2008Sakaguchi S. Yamaguchi T. Nomura T. Ono M. Cell. 2008; 133: 775-787Abstract Full Text Full Text PDF PubMed Scopus (3679) Google Scholar). Recent studies have shown that Foxp3+ Treg cells are able to sense cytokine signals in the environment and further differentiate to control specific type of inflammation via expressing transcription factors specifically associated with the differentiation and function of Th cell subsets. In this issue of Immunity, Koch et al., 2012Koch M.A. Thomas K.N. Perdue N.R. Smigiel K.S. Srivastava S. Campbell D.J. Immunity. 2012; 37 (this issue): 501-510Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar and Hall et al., 2012Hall A.O. Beiting D.P. Tato C. John B. Oldenhove G. Gonzalez Lombana C. Harms Pritchard G. Silver J.S. Bouladoux N. Stumhofer J.S. et al.Immunity. 2012; 37 (this issue): 511-523Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar demonstrate that T-bet+ Treg cells, one of such specialized Treg cell subpopulations, are induced in a STAT1-dependent manner by exposure to the cytokine IFN-γ or IL-27 and that each cytokine has distinct roles in driving T-bet+ Treg cells at inflammation sites. The transcription factor T-bet, normally required for Th1 cell development, is upregulated in Treg cells in response to IFN-γ, and T-bet-deficient Treg cells fail to rescue Foxp3-deficient mice from Th1 cell-mediated inflammatory disease (Koch et al., 2009Koch M.A. Tucker-Heard G. Perdue N.R. Killebrew J.R. Urdahl K.B. Campbell D.J. Nat. Immunol. 2009; 10: 595-602Crossref PubMed Scopus (919) Google Scholar). T-bet induces the Th1 cell-associated chemokine receptor CXCR3, which enables the T-bet+ Treg cells to migrate to a type 1 inflammation site and suppress local Th1 cell immune responses. Similarly IRF4+ Treg cells control type 2 inflammation: Treg-specific deletion of Irf4, which is critical for Th2 cell differentiation, results in the failure of these Treg cells to efficiently suppress Th2 cell-mediated immunopathology (Zheng et al., 2009Zheng Y. Chaudhry A. Kas A. deRoos P. Kim J.M. Chu T.T. Corcoran L. Treuting P. Klein U. Rudensky A.Y. Nature. 2009; 458: 351-356Crossref PubMed Scopus (715) Google Scholar). In addition, Treg cell-specific deficiency of the transcription factor STAT3, which is essential for proper development of Th17 cells, fails to suppress Th17 cell-mediated disease, indicating the role of STAT3+ Treg cells in controlling Th17 cell immune responses (Chaudhry et al., 2009Chaudhry A. Rudra D. Treuting P. Samstein R.M. Liang Y. Kas A. Rudensky A.Y. Science. 2009; 326: 986-991Crossref PubMed Scopus (777) Google Scholar). Thus, the ability of Foxp3+ Treg cells to control different types of Th cell responses crucially depends on their expression of specific Th cell-associated transcription factors. Key issues are then how they acquire such inflammation type-specific suppressive activities and how the activities are maintained during inflammation. In this issue, Koch et al., 2012Koch M.A. Thomas K.N. Perdue N.R. Smigiel K.S. Srivastava S. Campbell D.J. Immunity. 2012; 37 (this issue): 501-510Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar have investigated the molecular pathway leading to the upregulation of T-bet in Foxp3+ Treg cells and explored possible mechanisms by which T-bet+ Treg cell function is maintained in Th1 cell-polarizing inflammatory environments. They showed that activation of STAT1 by IFN-γ derived from activated Th1 cells induced T-bet expression in Treg cells. Notably, despite similar induction of CXCR3 expression in both Foxp3+ and Foxp3− T cells via T-bet activation, the levels of IL-12 receptor expression were different between the two populations. The expression of the receptor component IL-12Rβ2, which is induced in naive T cells after STAT1 and T-bet activation, was refractory to T-bet expression in Foxp3+ Treg cells in part because of altered epigenetic status of Il12rb2 locus in Treg cells. This prevented T-bet+ Treg cells from completing IL-12-STAT4-dependent Th1 cell differentiation and thereby ensured their maintenance of stable suppressive function without producing pro-inflammatory Th1 cytokines (Figure 1). Hall et al., 2012Hall A.O. Beiting D.P. Tato C. John B. Oldenhove G. Gonzalez Lombana C. Harms Pritchard G. Silver J.S. Bouladoux N. Stumhofer J.S. et al.Immunity. 2012; 37 (this issue): 511-523Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar showed that not only IFN-γ but also IL-27 was able to activate STAT1 in Treg cells, promote their expression of T-bet and CXCR3, and expand such T-bet+CXCR3+ Treg cells. Previous studies showed that IL-27, an inhibitory cytokine in the setting of autoimmunity and inflammation, did not alter Treg cell suppressive activity and that the frequency of Treg cells was not significantly changed in IL-27Ra-defiecient mice (Villarino et al., 2003Villarino A. Hibbert L. Lieberman L. Wilson E. Mak T. Yoshida H. Kastelein R.A. Saris C. Hunter C.A. Immunity. 2003; 19: 645-655Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar). Interestingly, Hall et al., 2012Hall A.O. Beiting D.P. Tato C. John B. Oldenhove G. Gonzalez Lombana C. Harms Pritchard G. Silver J.S. Bouladoux N. Stumhofer J.S. et al.Immunity. 2012; 37 (this issue): 511-523Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar showed that IL-27 deficiency resulted in significant reduction of T-bet+CXCR3+ Treg cells in the gut-associated lymphoid tissues (GALTs), but not in the spleen, during oral Toxoplasma gondii infection, which induced Th1 cell-dominant immune responses. In contrast, neutralization of IFN-γ reduced the expression of T-bet and CXCR3 in splenic Treg cells but not in Treg cells in the GALT of infected mice. Moreover, Treg cells exposed to IL-27 had distinct transcriptional profiles compared with those exposed to IFN-γ. These data collectively highlighted distinct roles of IFN-γ and IL-27 for induction of T-bet+ Treg cells and a dominant contribution of IL-27 at the sites of ongoing Th1 cell inflammation. These new findings of cytokine-induced Treg cell differentiation in the periphery have important implications regarding how Treg cells control specific types of inflammation. The results by Koch et al., 2012Koch M.A. Thomas K.N. Perdue N.R. Smigiel K.S. Srivastava S. Campbell D.J. Immunity. 2012; 37 (this issue): 501-510Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar and Hall et al., 2012Hall A.O. Beiting D.P. Tato C. John B. Oldenhove G. Gonzalez Lombana C. Harms Pritchard G. Silver J.S. Bouladoux N. Stumhofer J.S. et al.Immunity. 2012; 37 (this issue): 511-523Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar indicate that the guidance of Treg cells to type 1 inflammation sites via IFN-γ- or IL-27-dependent expression of CXCR3 is critical for specifically controlling Th1 cell immune responses even if every Treg cell has a common key mechanism of suppression, for example, CTLA-4-dependent modification of antigen-presenting cell function. It remains to be determined whether similar mechanisms are also operative in other inflammation type-specific Treg cells, for example, whether Treg cells expressing IRF4 control type 2 inflammation via IRF4-dependent expression of CCR8. In addition to the effects on Treg cell migration to inflammation sites, cytokines may control Treg cell suppressive function. For example, IL-27 induced IL-10 production in T cells and Treg cells. T-bet+ Treg cells, whether they were induced by IFN-γ or IL-27, abundantly produced IL-10, which was required for their suppression of type 1 inflammation in T. gondii infection. IL-10 is also produced by chronically stimulated Th1 cells in T. gondii infection (Jankovic et al., 2007Jankovic D. Kullberg M.C. Feng C.G. Goldszmid R.S. Collazo C.M. Wilson M. Wynn T.A. Kamanaka M. Flavell R.A. Sher A. J. Exp. Med. 2007; 204: 273-283Crossref PubMed Scopus (476) Google Scholar). It is thus likely that a cytokine not only controls cell migration of both Th and Treg cells but also confers suppressive or anti-inflammatory function on each population, thus dampening inflammation in Th cell-intrinsic and -extrinsic manners. It is controversial whether Foxp3+ Treg cells at a particular inflammation site bear a plasticity to differentiate into non-Treg cells, especially into proinflammatory Th cells, via losing Foxp3 expression. The conversion could be harmful because Foxp3 Treg cells are supposed to be more self-reactive in antigen specificity. Koch et al., 2012Koch M.A. Thomas K.N. Perdue N.R. Smigiel K.S. Srivastava S. Campbell D.J. Immunity. 2012; 37 (this issue): 501-510Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar showed that repression of IL-12Rβ2 expression in Treg cells prevented their conversion to Th1 effector T cells. Foxp3 binding sites were not found in the adjacent regions of the Il12rb2 locus (Zheng et al., 2007Zheng Y. Josefowicz S.Z. Kas A. Chu T.T. Gavin M.A. Rudensky A.Y. Nature. 2007; 445: 936-940Crossref PubMed Scopus (692) Google Scholar), and that deletion of Foxp3 in Treg cells failed to upregulate IL12Rβ2 expression, indicating that the repression of IL-12Rβ2 expression is a Foxp3-independent program of Treg cell differentiation. This cytokine-dependent and Foxp3-independent maintenance of functional or cell lineage stability of Treg cells can be exploited to generate and maintain functionally stable Treg cells for clinical use. Further investigation of how cytokines and Th cell-specific transcription factors regulate the function and differentiation of Foxp3+ Treg cells is necessary for better control of a variety of inflammation. T-bet+ Treg Cells Undergo Abortive Th1 Cell Differentiation due to Impaired Expression of IL-12 Receptor β2Koch et al.ImmunitySeptember 6, 2012In BriefFoxp3+ regulatory T (Treg) cells limit inflammatory responses and maintain immune homeostasis. Although comprised of several phenotypically and functionally distinct subsets, the differentiation of specialized Treg cell populations within the periphery is poorly characterized. We demonstrate that the development of T-bet+ Treg cells that potently inhibit T helper 1 (Th1) cell responses was dependent on the transcription factor STAT1 and occurred directly in response to interferon-γ produced by effector T cells. Full-Text PDF Open Archive
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