Abstract
Foxp3+CD4+ regulatory T (Treg) cells are essential for preventing fatal autoimmunity and safeguard immune homeostasis in vivo. While expression of the transcription factor Foxp3 and IL-2 signals are both required for the development and function of Treg cells, the commitment to the Treg cell lineage occurs during thymic selection upon T cell receptor (TCR) triggering, and precedes the expression of Foxp3. Whether signals beside TCR contribute to establish Treg cell epigenetic and functional identity is still unknown. Here, using a mouse model with reduced IL-2 signaling, we show that IL-2 regulates the positioning of the pioneer factor SATB1 in CD4+ thymocytes and controls genome wide chromatin accessibility of thymic-derived Treg cells. We also show that Treg cells receiving only low IL-2 signals can suppress endogenous but not WT autoreactive T cell responses in vitro and in vivo. Our findings have broad implications for potential therapeutic strategies to reprogram Treg cells in vivo.
Highlights
Foxp3+CD4+ regulatory T (Treg) cells are essential for preventing fatal autoimmunity and safeguard immune homeostasis in vivo
Laboratory (JacksLab) in 2009, referred to as Ccr2−/− 2009, we observed that CD4+ Foxp3+ Treg cells in primary and secondary lymphoid organs and blood, displayed low to no cell-surface expression of the IL-2Rα/CD25 compared to Treg cells from wild type (WT) B6 cell frequency counterparts (WT) (Supplementary Fig. 1a). among CD4+ T cells was reduced in spleens
Our data support a role for IL-2 in defining the epigenetic identity of Foxp3+ Treg cells, which appears largely independent of Foxp[3]
Summary
Foxp3+CD4+ regulatory T (Treg) cells are essential for preventing fatal autoimmunity and safeguard immune homeostasis in vivo. While the Foxp[3] TF is required to maintain peripheral Treg cell identity and functions, it is not sufficient per se to confer the functional attributes of Treg cells[12,16,24], consistent with twothirds of the Treg cell transcriptional signature that cannot be induced by ectopic expression using Foxp3Gfp knock-in/out of Foxp[3] reporter imn iTceconivncewllhs1ic4h,25.GSFtuPd+i/e+s thymocytes lacked functional Foxp[3], showed that Foxp[3] acts to amplify and fix pre-established molecular features of Treg cells acquired during thymic selection but prior Foxp[3] expression[14]. Foxp[3] overwhelmingly binds to pre-existing genome-wide enhancers in thymocytes committed to become Treg cells during positive selection[26] These findings suggest that TCR-induces epigenetic modifications independently of Foxp[3] but likely to involve other transcriptional regulators predefining Treg cell identity. Two recent reports provided mechanistic evidence for this concept[27,28] by showing (i) that the epigenetic modifier
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