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

Abstract

Previously, we showed that CD11c defines a novel subset of CD8 1 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 surfaceÀ CD8 1 T cells and undergoes robust expansion in an antigen-and 4-1BB (CD137)-dependent manner. CD11c 1 CD8 1 T cells exist in naïve mice (o3%) with limited suppressive activity. Once activated, they suppress CD4 1 T cells in vivo and in vitro. Suppression of CD4 1 by CD11c 1 CD8 1 T cells is related to an increase in IDO activity induced in competent cells via the general control non-derepressible-2 pathway. CD11c 1 CD8 1 T cells are refractory to the effect of IDO but constrict in a novel 1-methyl D,L-tryptophandependent 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 1 CD8 1 T-cell subpopulation that has many signature features of Treg.

Small intestine CD11c+CD8+T cells suppress CD4+T cell-induced immune colitis

“…In this study, SI CD11c ϩ CD8 ϩ T cells potently induced colitis protection, compared with other studies in which effective numbers of CD8 ϩ T cells from peripheral compartments required 4-to 80-fold greater numbers (1 to 20 ϫ 10 6 cells) for colitis protection (10,28,36,46,47) or other autoimmune diseases (14,26,38,45). Both cytolytic and noncytolytic mechanisms of immunoregulation have been reported for regulatory CD8 ϩ T cells, and those displayed by SI CD11c ϩ CD8 ϩ T cells remain to be determined.…”

“…Finally, recent studies of nonmucosal CD11c ϩ CD8 ϩ T cells reported that their suppression of inflammatory CD4 ϩ T cells required indoleamine 2,3-dioxygenase (IDO) induced by CD137 (4 -1BB), a TNF family member involved with CD28-independent T-cell activation (45). As a tryptophan-catabolizing enzyme, IDO plays a variety of important roles in immune tolerance, tumor resistance, chronic infections, and autoimmune disease (29).…”

CD11chighCD8+ Regulatory T Cell Feedback Inhibits CD4 T Cell Immune Response via Fas Ligand–Fas Pathway

“…For example, it was found that CD11c + CD8 + T cells possess higher levels of LCMVspecific killing activity than CD11c 2 CD8 + T cells (42); anti-4-1BB mAb administration to B16F10 melanoma-bearing mice induced potent expansion of CD11c + CD8 + T cells in parallel with suppression of tumors (43,44). However, CD11c high CD8 + T cells might be induced and expanded only in unique conditions, such as on day 8 of L. monocytogenes infection in this study, or after agonistic anti-4-1 BB mAb inoculation in autoimmune or inflammatory disorders (25)(26)(27).…”

CD8+ Tregs in autoimmunity: learning “self”-control from experience

“…CD11c ? T cells can be detected in the periphery and constitute \3% of the peripheral T cell population, although they appear as naïve cells (based on their CD44 and CD62L profiles) and do not present appreciable suppressive activity in vitro [103]. These cells, however, do express significantly elevated levels of CD28 and CD103 relative to their CD11c-negative counterparts.…”

“…T cells was not established, and the possibility of anti-4-1BB acting on other cell types was not excluded. A subsequent study by Vinay et al [103] showed that CD8 ? CD11c ?…”