Abstract
Signaling events affecting thymic selection of un-manipulated polyclonal natural CD25+foxp3+ regulatory T cells (nTreg) have not been established ex vivo. Here, we report a higher frequency of phosphorylated STAT-5 (pSTAT-5) in nTreg cells in the adult murine thymus and to a lesser extent in the periphery, compared to other CD4+CD8− subsets. In the neonatal thymus, the numbers of pSTAT-5+ cells in CD25+foxp3− and nTreg cells increased in parallel, suggesting that pSTAT-5+CD25+foxp3− cells might represent the precursors of foxp3+ regulatory T cells. This “specific” pSTAT-5 expression detected in nTreg cells ex vivo was likely due to a very recent signal given by IL-2/IL-15 cytokines in vivo since (i) it disappeared rapidly if cells were left unstimulated in vitro and (ii) was also observed if total thymocytes were stimulated in vitro with saturating amounts of IL-2 and/or IL-15 but not IL-7. Interestingly, STAT-5 activation upon IL-2 stimulation correlated better with foxp3 and CD122 than with CD25 expression. Finally, we show that expression of an endogenous superantigen strongly affected the early Treg cell repertoire but not the proportion of pSTAT-5+ cells within this repertoire. Our results reveal that continuous activation of the CD122/STAT-5 signaling pathway characterize regulatory lineage differentiation in the murine thymus.
Highlights
Natural regulatory CD4+CD25+foxp3+ T cells are generated in the thymus of mice and humans early in their ontogeny [1,2,3]
To investigate the association between phosphorylated STAT-5 (pSTAT-5) and foxp3 expression in adult mice, we quantified the frequencies of pSTAT-5+ cells in various CD4+ subsets defined by CD25 and foxp3 expression in the thymus and in the periphery of adult C57BL/6 mice
Very low frequencies (,0.1%) of pSTAT-5+ cells were observed in CD252foxp32 cells, which comprise the majority of CD4+CD82 cells of the thymus
Summary
Natural regulatory CD4+CD25+foxp3+ T cells (nTreg) are generated in the thymus of mice and humans early in their ontogeny [1,2,3]. These nTreg cells are in charge of controlling peripheral T cells that have escaped negative selection in the thymus and that could pose a threat to the integrity of healthy tissues. Similar cases of autoimmunity have been found in nTreg cells that have spontaneously lost foxp expression [8]. A better understanding of foxp regulation is needed for translating the huge therapeutic potential of nTreg cells to the clinic
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