Figure 1.

T regulatory type 1 (Tr1)-mediated suppression in vivo. In steady-state condition, Tr1 cells reside in the spleen and circulate in the periphery. During inflammation, Tr1 cells are recruited to the site of tissue injury (i.e., after infections, autoimmune reactions, or transplantation) and are activated by professional antigen-presenting cells [APCs; dendritic cells (DCs)] via their T cell receptor, thus by their cognate antigen (Ag). Upon activation, Tr1 cells secrete IL-10 and TGF-β and (1) directly inhibit effector T cell (i.e., Th1 and Th17 cells) proliferation and pro-inflammatory cytokines production and (2) indirectly inhibit effector T cells by modulating professional APCs (i.e., downregulation of costimulatory and HLA class II expression and inhibition of pro-inflammatory cytokine secretion). (3) Tr1 cells can suppress effector T cells by cell-to-cell contact-mediated mechanisms, (4) suppress CD8⁺ T cell responses (i.e., proliferation and IFN-γ production), and (5) mediate bystander suppression by specifically killing professional APCs [DC or macrophages (M)], thus preventing naive T (Tn) cell priming and reactivation of effector T cells (i.e., Th1 and Th17 cells). Concomitantly, (6) Tr1 cells via IL-10 and TGF-β promote the induction of tolerogenic DC and anti-inflammatory macrophages (M2), which in turn promote de novo induction of Tr1 cells and T regulatory cells (Tregs), restoring tissue homeostasis and promoting long-term tolerance.