Induction of T cell unresponsiveness by anti‐CD3 antibodies occurs independently of co‐stimulatory functions

Publisher Website
Google Scholar
Abstract
Antibodies to the T cell receptor (TcR)‐associated CD3 molecules represent potent immunosuppressive agents in vivo in both human and animals models, in spite of their well‐characterized mitogenic properties. We demonstrate in this report that antibodies to the B7.2 molecule inhibit IL‐2 production in vivo caused by anti‐CD3 administration, suggesting that anti‐CD3 monoclonal antibodies (mAb) stimulate naive T cells in vivo in a co‐stimulation‐dependent fashion. To characterize better the mechanisms by which antibodies to CD3 induce antigen unresponsiveness in naive T cells, we developed a model of activation‐induced T cell unresponsiveness in vitro. Our data indicate that following interaction with mitogenic anti‐CD3 mAb in vitro, naive purified CD4+ T cells become refractory to a further stimulus. This unresponsive state develops independently of co‐stimulatory functions, as neither B7‐expressing antigen‐presenting cells nor anti‐CD28 mAb are able to prevent anergy induction in this model. We therefore conclude that induction of unresponsiveness in naive T cells by anti‐CD3 mAb is not a consequence of co‐stimulus‐deficient stimulation, but may develop following a productive response both in vivo and in vitro. Unresponsive T cells display a defective calcium mobilization upon TcR triggering, suggesting that anergy is maintained in these cells through receptor desensitization. The potential role of co‐stimulation‐independent TcR desensitization in the down‐regulation of immune responses in vivo is briefly discussed.