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The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery
Shimon Sakaguchi
Laboratory for Immunopathology, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
Address correspondence to: Shimon Sakaguchi, Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-3888; Fax: 81-75-751-3820; E-mail: shimon@frontier.kyoto-u.ac.jp.
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Published November 1, 2003 - More info
J Clin Invest. 2003;112(9):1310–1312. https://doi.org/10.1172/JCI20274.
© 2003 The American Society for Clinical Investigation
The immune system discriminates between self and non-self, maintaining immunologic self-tolerance (i.e., unresponsiveness to self-constituents). It is known that potentially hazardous self-reactive T and B cells are clonally deleted at immature stages of their development or inactivated upon encounter with self-antigens in the periphery. There is now accumulating evidence that, in addition to these passive mechanisms of self-tolerance, a population of CD4+ T cells, called regulatory T cells (TR cells), engage in the maintenance of peripheral self-tolerance by actively suppressing the activation and expansion of self-reactive T cells (1–3). The majority, if not all, of such naturally occurring CD4+ TR cells constitutively express CD25 (IL-2 receptor α chain) in the physiologic state. Indeed, removal of CD25+CD4+ T cells, which constitute 5–10% of CD4+ T cells in rodents and humans, leads to spontaneous development of various autoimmune diseases in otherwise normal mice (4). The removal of CD25+CD4+ TR cells also triggers excessive or misdirected immune responses to microbial antigens, causing immunopathology, such as inflammatory bowel disease (IBD), due to hyper-reaction of the remaining T cells to commensal bacteria in the intestine (3).
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The origin and the developmental pathway of FOXP3-expressing TR cells
The discovery of FOXP3/Foxp3 as a specific and stable marker for natural TR cells now makes it possible to determine the origin and the developmental pathway of TR cells in humans, as reported by Walker et al. in this issue of the JCI (14). It has been shown, mainly in rodents, that the normal thymus continuously produces CD25+CD4+ TR cells as a functionally mature T cell subpopulation that recognizes a broad repertoire of self- and non-self antigens, and that abrogation of the thymic production of TR cells leads to the development of autoimmune disease (1–3). Walker et al. (14) show that CD25+CD4+ T cells in the peripheral blood lymphocytes express FOXP3 and are capable of suppressing the activation and expansion of other T cells in vitro, as shown in rodents (11–13). Furthermore, they show that, in contrast with murine Foxp3 expression, activation of CD25–CD4+ T cells by T cell receptor (TCR) stimulation induces FOXP3 expression, and that FOXP3-expressing T cells derived from CD25–CD4+ T cells are equally as suppressive as natural CD25+CD4+ TR cells (Figure 1) (14). This interesting finding suggests two possibilities regarding the origin of CD25+CD4+ TR cells. One is that naive T cells can differentiate to CD25+CD4+ TR cells upon TCR stimulation, in a manner similar to that in which the expression of the transcription factors T-bet and GATA-3 instruct naive T cells to differentiate to Th1 and Th2 cells, respectively (15, 16). Another possibility is that some of the functionally mature TR cells produced by the thymus are CD25– or lose CD25 expression with retention of their suppressive function, as has been shown in rodents (17–19). Such CD25– TR cells may become CD25+ upon activation, especially when other T cells respond to antigen stimulation, and IL-2 secreted by them may trigger the expansion of TR cells. Given the specific expression of FOXP3 in TR cells whether they are of thymic or peripheral origin, it remains to be determined whether other T cells with regulatory functions, such as IL-10–secreting Tr1 or TGF-β–secreting Th3 cells, may also express FOXP3 (20).
Figure 1The normal thymus produces FOXP3-expressing CD25+CD4+ TR cells. Some of the naive CD25–CD4+ T cells may also differentiate to FOXP3-expressing CD25+CD4+ TR cells in the periphery. These TR cells suppress the activation and expansion of self-reactive T cells that may cause autoimmune disease. Genetic defects of FOXP3 cause IPEX due to developmental or functional defects of TR cells. Adapted with permission from Nature Immunology (21).
Besides self-tolerance and autoimmunity, evidence is now accumulating that natural CD4+ TR cells actively engage in negative control of a broad spectrum of immune responses to quasi-self or non-self antigens, as in tumor immunity, organ transplantation, allergy, and microbial immunity (1–3). With FOXP3 as a useful tool for investigating TR cells, further characterization of their developmental pathways will facilitate better control of pathologic as well as physiologic immune responses by expansion or reduction of TR cell populations.
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