TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs

Modified anti-CD3 mAbs are emerging as a possible means of inducing immunologic tolerance in settings including transplantation and autoimmunity such as in type 1 diabetes. In a trial of a modified anti-CD3 mAb [hOKT3 gamma 1(Ala-Ala)] in patients with type 1 diabetes, we identified clinical responders by an increase in the number of peripheral blood CD8(+) cells following treatment with the mAb. Here we show that the anti-CD3 mAb caused activation of CD8(+) T cells that was similar in vitro and in vivo and induced regulatory CD8(+)CD25(+) T cells. These cells inhibited the responses of CD4(+) cells to the mAb itself and to antigen. The regulatory CD8(+)CD25(+) cells were CTLA4(+) and Foxp3(+) and required contact for inhibition. Foxp3 was also induced on CD8(+) T cells in patients during mAb treatment, which suggests a potential mechanism of the anti-CD3 mAb immune modulatory effects involving induction of a subset of regulatory CD8(+) T cells.