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CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors

Kalekar, LA;Schmiel, SE;Nandiwada, SL;Lam, WY;Barsness, LO;Zhang, N;Stritesky, GL;Malhotra, D;Pauken, KE;Linehan, JL;O'Sullivan, MG;Fife, BT;Hogquist, KA;Jenkins, MK;Mueller, DL;

The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation.