Induction of T cell unresponsiveness by anti-CD3 antibodies occurs independently of co-stimulatory functions.
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.
Andris
F
F
Laboratoire de Physiologie Animale, Université Libre de Bruxelles, Belgium.
Van Mechelen
M
M
De Mattia
F
F
Baus
E
E
Urbain
J
J
Leo
O
O
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology*; D002478:Cells, Cultured; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell