Origins and functional basis of regulatory CD11c+CD8+ T cells

Previously, we showed that CD11c defines a novel subset of CD8⁺ T cells whose in vivo activity is therapeutic for arthritis; however, the mechanisms directing their development, identity of their precursors, and basis of their effector function remain unknown. Here, we show that the novel subset develops from CD11c^surface?CD8⁺ T cells and undergoes robust expansion in an antigen‐ and 4‐1BB (CD137)‐dependent manner. CD11c⁺CD8⁺ T cells exist in naïve mice (<3%) with limited suppressive activity. Once activated, they suppress CD4⁺ T cells in vivo and in vitro. Suppression of CD4⁺ by CD11c⁺CD8⁺ T cells is related to an increase in IDO activity induced in competent cells via the general control non‐derepressible‐2 pathway. CD11c⁺CD8⁺ T cells are refractory to the effect of IDO but constrict in a novel 1‐methyl D ,L ‐tryptophan‐dependent mechanism resulting in reversal of their suppressive effects. Thus, our data uncover, for the first time, the origin, development, and basis of the suppressive function of this novel CD11c⁺CD8⁺ T‐cell subpopulation that has many signature features of Treg.