CTLA-4.Ig converts naive CD4+CD25- t cells into CD4+CD25+ regulatory t cells

CTLA-4.Ig was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4.Ig, in combination with TCR ligation, has the additional capacity to convert naive CD4(+)CD25(-) T cells into Foxp3(+) regulatory T (T-reg) cells, as well as to expand their numbers. The CD4(+)CD25(+)Foxp3(+) T-reg generated by CTLA-4.Ig treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4.Ig increases the percentage of CD4(+)CD25(hi)Foxp3(+) cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4(+)CD25(-) T cells into T-reg cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4.Ig-driven T-reg induction may be predicated upon active CTLA-4.Ig to B7-2 signaling within APC, which elicits from them T-reg-inducing potential. These findings extend CTLA-4.Ig's functional repertoire, and at the same time, reinforce the concept that T cell anergy and active suppression are not entirely distinct processes and may be linked by some common molecular triggers.