Affinity for self antigen selects regulatory T cells with distinct functional properties

How regulatory T cells (T(reg) cell) control lymphocyte homeostasis is not fully understood. Here we identify two T(reg) cell populations with differing degrees of self-reactivity and distinct regulatory functions. Triple(hi) (GITR(hi)PD-1(hi)CD25(hi)) T(reg) cell are highly self-reactive and control lympho-proliferation in peripheral lymph nodes. Triple(lo) (GITR(lo)PD-1(lo)CD25(lo)) T(reg) cells are less self-reactive and limit development of colitis by promoting conversion of CD4(+) T(conv) cells into induced T(reg) cells (iT(reg) cells). Although Foxp3-deficient (scurfy) mice lack T(reg) cells, they contain Triple(hi)-like and Triple(lo)-like CD4(+) T cells with distinct pathological properties. Scurfy Triple(hi)CD4(+)T cells infiltrate the skin whereas scurfy Triple(lo)CD4(+)T cells induce colitis and wasting disease. These findings indicate that T cell receptor affinity for self-antigens drives the differentiation of Tregs into distinct subsets with non-overlapping regulatory activities.