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• W2034872857 abstract "Regulatory T (Treg) cells are thought to be susceptible to conversion into effector T cells. In this issue of Immunity, Miyao et al., 2012Miyao T. Floess S. Setoguchi R. Luche H. Fehling H.J. Waldmann H. Huehn J. Hori S. Immunity. 2012; 36 (this issue): 262-275Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar provide evidence that the apparent plasticity of murine Foxp3+ Treg cells is largely restricted to a defined subset of poorly committed Foxp3+ cells. Regulatory T (Treg) cells are thought to be susceptible to conversion into effector T cells. In this issue of Immunity, Miyao et al., 2012Miyao T. Floess S. Setoguchi R. Luche H. Fehling H.J. Waldmann H. Huehn J. Hori S. Immunity. 2012; 36 (this issue): 262-275Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar provide evidence that the apparent plasticity of murine Foxp3+ Treg cells is largely restricted to a defined subset of poorly committed Foxp3+ cells. Proper functioning of the immune system implies a tightly balanced regulation of effector mechanisms to avoid autoimmunity and immunopathology. A variety of control mechanisms have been identified, comprising negative feedback circuits affecting activation, survival, or functioning of effector cells. Regarding the discrimination of self from non-self, central tolerance was initially thought to be the key in avoiding autoimmunity, but the (re)discovery of specific T cells populations, now called regulatory T (Treg) cells, that can suppress self-reactive responses and that are characterized by the expression of the transcription factor Foxp3 has led to the insight that dominant tolerance mediated by Foxp3+CD4+ Treg cells is a vital component of the immunological balance. Not surprisingly, this population of Foxp3+ T cells has attracted much interest, including that of clinical scientists considering transfer of Treg cells as a valuable therapy to control life-threatening graft-versus-host disease, to improve acceptance of transplanted organs, or to suppress autoimmunity in a more specific way than by currently used therapies. However, such therapies would encounter unpredictable risks if the cell type transferred would be unstable or even could convert into effector cells producing inflammatory cytokines, as some recent experimental data suggested. The question of whether Foxp3+ Treg cells represent a stable lineage or display a substantial degree of plasticity is therefore a matter of considerable importance, particularly because previous investigations resulted in controversial conclusions. What is the evidence that Foxp3+ Treg cells are defined lineages? No doubt that T cells of a number of functional states can have suppressive actions. IL-10-producing CD4+ T cells, for example, clearly have an important regulatory function, but so far evidence is rather pointing to contextual acquisition of this property, optional both for cells of the Treg cell lineage as well as for multiple inflammatory phenotypes such as Th1, Th2, or Th17 cells. IL-10-producing cells lack a clonal commitment to produce IL-10 and apparently do not establish an IL-10-specific cytokine memory; i.e., these cells do not fulfill the definitions of a stable cell lineage (Dong et al., 2007Dong J. Ivascu C. Chang H.D. Wu P. Angeli R. Maggi L. Eckhardt F. Tykocinski L. Haefliger C. Möwes B. et al.J. Immunol. 2007; 179: 2389-2396Crossref PubMed Scopus (45) Google Scholar). The situation seemed to be different for Foxp3+ Treg cells, which is believed to develop autonomously as a separate lineage within the thymus and to harbor a high degree of stability both in vitro and in vivo. However, upon the emergence of more and more studies providing evidence that Foxp3+ cells could give rise to Foxp3− and even effector cytokine+ progeny, especially in an inflammatory environment, the possibility had to be considered that also Foxp3+ Treg cells could show plasticity and become inactivated or even converted into effector cells. The straightforward approach to clarify the issue of plasticity appears to be sorting to highest possible purity and monitoring the stability of Foxp3 expression, suppressive properties, and methylation status of an evolutionary conserved element within the Foxp3 locus (TSDR, Treg cell-specific demethylated region) as marker for a stable Treg cell phenotype during in vitro or in vivo expansion. But how can we determine purity if an unequivocal marker for Treg cells does not exist? Studies aiming at expanding Treg cells for application in graft-versus-host disease have observed striking differences in the apparent stability of Foxp3+ cells during in vitro expansion, depending upon the marker combination used for sorting (Hoffmann et al., 2009Hoffmann P. Boeld T.J. Eder R. Huehn J. Floess S. Wieczorek G. Olek S. Dietmaier W. Andreesen R. Edinger M. Eur. J. Immunol. 2009; 39: 1088-1097Crossref PubMed Scopus (260) Google Scholar); this can be interpreted as a different degree of plasticity among Treg cell subsets or, alternatively, as an outgrowth of a minor subset of cells not completely committed to a stable Treg cell lineage. Outgrowth, but not heterogeneity, of the starting population could be excluded in the above-mentioned study by cloning; yet still loss of Foxp3 expression is not necessarily indicative of loss of Treg cell identity. Indeed, the question of whether Foxp3 expression is sufficient to define Treg cell identity is not trivial. Although a number of investigations have underlined the central importance of Foxp3 expression for the suppressive program, the notion that Foxp3 is the master transcription factor of Treg cells is probably a (popular) oversimplification. Notably in the human system, Foxp3 expression without the acquisition of suppressive activity is routinely observed upon activation of CD4+ T cells. But even in the murine system, where Foxp3 expression appears to be more restricted, several studies provide evidence that commitment to the Treg cell lineage occurs before induction of and might actually be independent of Foxp3 expression. Moreover, the unique transcriptome of Treg cells can only partly be explained by the impact of Foxp3 on gene activity (Hill et al., 2007Hill J.A. Feuerer M. Tash K. Haxhinasto S. Perez J. Melamed R. Mathis D. Benoist C. Immunity. 2007; 27: 786-800Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar), and committed Foxp3− Treg cell precursors prone to upregulate Foxp3 expression can be identified in both thymic and peripheral subpopulations of CD25+Foxp3−CD4+ T cells (Lio and Hsieh, 2008Lio C.W. Hsieh C.S. Immunity. 2008; 28: 100-111Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar, Schallenberg et al., 2010Schallenberg S. Tsai P.Y. Riewaldt J. Kretschmer K. J. Exp. Med. 2010; 207: 1393-1407Crossref PubMed Scopus (62) Google Scholar). The study of Miyao et al., 2012Miyao T. Floess S. Setoguchi R. Luche H. Fehling H.J. Waldmann H. Huehn J. Hori S. Immunity. 2012; 36 (this issue): 262-275Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar in this issue of Immunity provides compelling evidence that in the murine system, Foxp3 expression is also more promiscuous and not completely indicative of a stable Treg cell lineage. By using a Foxp3-driven, Cre-mediated fate mapping approach that permanently marks all cells that had expressed Foxp3 at any time during their development, the authors could demonstrate that a sizeable fraction of cells can be detected that had only transiently expressed Foxp3 but later, as “exFoxp3” cells, can easily convert into effector cells under appropriate conditions, whereas a core population of committed Foxp3+ Treg cells exists that are stable and resistant to conversion into effector cells. Similar systems have been used previously but led to contrasting conclusions. In a BAC transgene-based system, a considerable emergence of exFoxp3 cells, especially under inflammatory conditions, has been observed, which was paralleled by the occurrence of cytokine-producing effector cells among them. This led to the authors' conclusion that at least a subset of Foxp3+ Treg cells displays plasticity and can be converted into effector T cells (Zhou et al., 2009Zhou X. Bailey-Bucktrout S.L. Jeker L.T. Penaranda C. Martínez-Llordella M. Ashby M. Nakayama M. Rosenthal W. Bluestone J.A. Nat. Immunol. 2009; 10: 1000-1007Crossref PubMed Scopus (967) Google Scholar). In contrast, an inducible system allowing snapshot labeling of Foxp3+ Treg cells during a defined time window did not reveal a major fraction of cells losing Foxp3 in adult mice. However, a minor fraction of exFoxp3 cells was also reported in this study (Rubtsov et al., 2010Rubtsov Y.P. Niec R.E. Josefowicz S. Li L. Darce J. Mathis D. Benoist C. Rudensky A.Y. Science. 2010; 329: 1667-1671Crossref PubMed Scopus (523) Google Scholar). Miyao et al., 2012Miyao T. Floess S. Setoguchi R. Luche H. Fehling H.J. Waldmann H. Huehn J. Hori S. Immunity. 2012; 36 (this issue): 262-275Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar now provide a framework of findings reconciling these data by showing that (1) “exFoxp3” cells represent a small but significant fraction of T cells in the adult that develop predominantly during early periods of life and along conversion of naive cells into (adaptive) Treg cells in the periphery under homeostatic conditions; (2) cells transiently expressing Foxp3 have a higher potential to expand than “true” Treg cells, especially under lymphopenic (IL-2-deficient) conditions; (3) a majority of exFoxp3 cells represents conventional T cells by phenotype, differentiation potential, and methylation status in the stability-determining TSDR of the foxp3 locus; and (4) a minority of exFoxp3 cells are committed Treg cells displaying transient downregulation of Foxp3 expression because of lack of appropriate T cell receptor (TCR) and/or IL-2 signaling while maintaining the demethylated TSDR status and rapidly reacquiring Foxp3 expression upon TCR stimulation (Figure 1). Thus, apparent plasticity of Foxp3+ Treg cells might largely be explained by heterogeneity of Foxp3-expressing cells. The use of single-cell assays, such as limiting-dilution approaches, seems attractive to further prove this assumption, yet might be difficult in the murine system because of the poor proliferation capacity of Treg cells. That dissociation between Foxp3 expression and those features defining a committed Treg cell lineage occurs more frequently among Foxp3+ cells induced in the periphery suggests that environmental conditions for the imprinting of a stable Treg cell lineage are favorable within the thymus. In contrast, peripherally induced Foxp3+ T cells display a whole spectrum of properties, from transient, functionally irrelevant Foxp3 expression via unstable Treg cells without epigenetic fixation (as in TGF-β-induced Treg cells) to fully stable Treg cells with demethylated TSDR induced by tolerogenic DEC205 vaccination (Polansky et al., 2008Polansky J.K. Kretschmer K. Freyer J. Floess S. Garbe A. Baron U. Olek S. Hamann A. von Boehmer H. Huehn J. Eur. J. Immunol. 2008; 38: 1654-1663Crossref PubMed Scopus (622) Google Scholar). These differences might especially be relevant for the gut mucosa as a dominant site of peripheral Treg cell induction. One key question remains to be answered: what are the signals that lead to the imprinting of a stable Treg cell phenotype? A variety of factors including TCR activation, CD28 costimulation, and IL-2 signaling have been suggested to contribute to the differentiation into Treg cells; however, the precise nature of signals leading to the selective demethylation of the Foxp3 locus are only incompletely understood (Klein and Jovanovic, 2011Klein L. Jovanovic K. Semin. Immunol. 2011; 23: 401-409Crossref PubMed Scopus (43) Google Scholar). Presently it is absolutely open whether specific second signals are instrumental or whether the decision between Treg cell commitment and differentiation into conventional T cells is a matter of defined signal strengths of the TCR in conjunction with supporting as well as counteracting environmental signals and cell-intrinsic developmental predispositions. Answering of these questions will not only be of central importance for the understanding of the origin of the Treg cell lineage, but also better define the conditions to be met when induction or expansion of Foxp3+ Treg cells for therapeutic application is intended. Plasticity of Foxp3+ T Cells Reflects Promiscuous Foxp3 Expression in Conventional T Cells but Not Reprogramming of Regulatory T CellsMiyao et al.ImmunityFebruary 9, 2012In BriefThe emerging notion of environment-induced reprogramming of Foxp3+ regulatory T (Treg) cells into helper T (Th) cells remains controversial. By genetic fate mapping or adoptive transfers, we have identified a minor population of nonregulatory Foxp3+ T cells exhibiting promiscuous and transient Foxp3 expression, which gave rise to Foxp3− (“exFoxp3”) Th cells and selectively accumulated in inflammatory cytokine milieus or in lymphopenic environments including those in early ontogeny. In contrast, Treg cells did not undergo reprogramming under those conditions irrespective of their thymic or peripheral origins. Full-Text PDF Open Archive" @default.
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• W2034872857 title "Regulatory T Cells Stay on Course" @default.
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