Affinity for self antigen selects T-reg cells with distinct functional properties.

Abstract

The manner in which regulatory T cells (T-reg cells) control lymphocyte homeostasis is not fully understood. We identified two T-reg cell populations with differing degrees of self-reactivity and distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) T-reg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR(lo)PD-1(lo)CD25(lo) (Triple(lo)) T-reg cells were less self-reactive and limited the development of colitis by promoting the conversion of CD4(+) T-conv cells into induced T-reg cells (iT(reg) cells). Although Foxp3-deficient (Scurfy) mice lacked T-reg cells, they contained Triple(hi)-like and Triple(lo)-like CD4(+) T cells with distinct pathological properties. Scurfy Triple(hi)CD4(+) T cells infiltrated the skin, whereas Scurfy. Triple(lo)CD4(+) T cells induced colitis and wasting disease. These findings indicate that the affinity of the T cell antigen receptor for self antigen drives the differentiation of T-reg cells into distinct subsets with non-overlapping regulatory activities.