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.