Immature dendritic cells convert anergic nonregulatory T cells into Foxp3-IL-10+ regulatory T cells by engaging CD28 and CTLA-4

Abstract

Anergic T cells can survive for long time periods passively in a hyporesponsive state without obvious active functions. Thus, the immunological reason for their maintenance is unclear. Here, we induced peptide-specific anergy in T cells from mice by coculturing these cells with immature murine dendritic cells (DCs). We found that these anergic, nonsuppressive IL-10-Foxp3-CTLA-4+CD25lowEgr2+ T cells could be converted into suppressive IL-10+Foxp3-CTLA-4+CD25highEgr2+ cells resembling type-1 Treg cells (Tr1) when stimulated a second time by immature DCs in vitro. Addition of TGF-β during anergy induction favored Foxp3+ Treg-cell induction, while TGF-β had little effect when added to the second stimulation. Expression of both CD28 and CTLA-4 molecules on anergic T cells was required to allow their conversion into Tr1-like cells. Suppressor activity was enabled via CD28-mediated CD25 upregulation, acting as an IL-2 sink, together with a CTLA-4-mediated inhibition of NFATc1/α activation to shut down IL-2-mediated proliferation. Together, these data provide evidence and mechanistical insights into how persistent anergic T cells may serve as a resting memory pool for Tr1-like cells.