A novel mechanism of action for anti-thymocyte globulin:: Induction of CD4+CD25+Foxp3+ regulatory T cells

T cell-depleting agents are being tested as part of clinical tolerance strategies in humans with autoimmunity and transplantation. The immunosuppressive activity of anti-thyrnocyte globulin (ATG) has been thought to result primarily from depletion of peripheral lymphocytes. Herein is reported for the first time that ATG but not anti-CD52 mAb (alemtuzumab) or the IL-21Z antagonists causes rapid and sustained expansion of CD4(+)CD25(+) T cells when cultured with human peripheral blood lymphocytes. These cells display enhanced expression of the regulatory markers glucocorticoid-induced TNF receptor, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and forkhead box P3 and efficiently suppress a direct alloimmune response of the original responder lymphocytes. It is interesting that the cells do not suppress memory responses to the recall antigen mumps. Ex vivo expansion of regulatory T cells is due mainly to conversion of CD4(+)CD25(+) into CD4(+)CD25(+) T cells and to a lesser degree to proliferation of natural CD4(+)CD25(+) T cells. The induction of regulatory T cells depends on production of Th2 cytokines in the generating cultures. These novel data suggest that ATG not only may promote expansion/ generation of regulatory T cells but also may be useful in future ex vivo expansion of these cells for cellular therapy in autoirnmunity and clinical transplantation.