Affinity for self antigen selects T_reg cells with distinct functional properties

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^hiPD-1^hiCD25^hi (Triple^hi) Treg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR^loPD-1^loCD25^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 zsuper> T cells infiltrated the skin, whereas Scurfy Triple^loCD4⁺ 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.