Downregulation of antigen-presenting cell functions after administration of mitogenic anti-CD3 monoclonal antibodies in mice

Antibodies against CD3 epsilon are widely used as immunosuppressive agents. Although it is generally assumed that these reagents exert their immunomod ulatory properties by inducing T-cell deletion and/or inactivation, their p recise mechanism of action remains to be elucidated. Using a murine model, we demonstrate in this report that administration of anti-CD3 epsilon antib odies causes the migration and maturation of dendritic cells (DC) in vivo, as determined by immunohistochemical analysis. This maturation/migration pr ocess was followed by selective loss of splenic DC, which resulted in a sel ective inhibition of antigen-presenting cell (APC) functions in vitro. Sple en cells from anti-CD3 epsilon-treated animals were unable to productively stimulate naive alloreactive T cells and Th1-like clones in response to ant igen, while retaining the ability to present antigen to a T-cell hybridoma and Th2 clones. Anti-CD3 epsilon treatment was found to induce a selective deficiency in the ability of spleen cells to produce bioactive interleukin- 12 in response to CD40 stimulation. APC dysfunction was not observed when n onmitogenic forms of anti-CD3 epsilon antibodies were used, suggesting that splenic DC loss was a consequence of in vivo T-cell activation. Nonmitogen ic anti-CD3 epsilon monoclonal antibodies were found to be less immunosuppr essive in vivo, raising the possibility that APC dysfunction contributes to anti-CD3 epsilon-induced immunomodulation, Collectively, these data sugges t a novel mechanism by which mitogenic anti-CD3 epsilon antibodies downregu late immune responses. (C) 1999 by The American Society of Hematology.