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

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