CTLA-4{middle dot}Ig converts naive CD4+CD25- T cells into CD4+CD25+ regulatory T cells

Abstract

CTLA-4 x 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 x 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 x Ig treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4 x 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 x Ig-driven T(reg) induction may be predicated upon active CTLA-4 x Ig to B7-2 signaling within APC, which elicits from them T(reg)-inducing potential. These findings extend CTLA-4 x 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.

CTLA4-Ig Preserves Thymus-Derived T Regulatory Cells

“…Furthermore, some experimental evidence suggested that the tolerogenic efficacy of costimulation blockade by CTLA4-Ig even critically depended on Foxp3 + T reg cells (40,41). The sources of T reg cells promoted by costimulation blockade included adaptive T reg cells (42), conversion of CD4 + CD25 + Foxp3 j cells to CD4 + CD25 + Foxp3 + cells (43), or as in the present study, thymus-derived T reg cells (24).…”

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

“…While one report suggests that abatacept therapy inhibits activation-induced cell death of Treg cells, which resulted in their increased proportion in the blood (24), others suggest that abatacept therapy diminishes the frequency of Treg cells in RA patients (25). Murine studies have also been equivocal, with systemic administration of CTLA-4Ig being reported as leading to an increase in CD41CD251 Treg cells (45). However, none of these studies could distinguish between natural or inducible Treg cells, as they used polyclonal T cell populations or peripheral blood.…”

De novo induction of platelet-specific CD4+CD25+ regulatory T cells from CD4+CD25− cells in patients with idiopathic thrombocytopenic purpura

“…Extensive data in mice have demonstrated that antigen-specific iTreg can be induced from previously nonregulatory CD4 ϩ CD25 Ϫ cells. [10][11][12][13] In humans, despite that a regulatory phenotype could be induced from CD4 ϩ CD25 Ϫ T cells, 14 there are few functional studies showing acquisition of suppressive activity by stimulated CD4 ϩ CD25 Ϫ T cells in healthy subjects. [15][16][17] Whether autoantigen-specific Treg could be converted from CD4 ϩ CD25 Ϫ T cells in patients with autoimmune diseases has not been reported.…”