Inhibition of T cell activation through down-regulation of TCR-CD3 expression mediated by an anti-CD90 Ab.
We are trying to develop new Abs that can manipulate CD4 T cell responses and are usable as immunosuppressive agents. To this end, we performed functional screening, in which we examined the effect of an Ab on the proliferation of mouse CD4 T cells upon activation. The Ab, LP5, inhibited the activation of CD4 T cells stimulated with an anti-CD3 Ab or peptide antigen. The Ab alone had no stimulatory effect on CD4 T cells. Biochemical experiments demonstrated that LP5 recognized the Thy-1 (CD90) molecule. Interestingly, the treatment of CD4 T cells with LP5 in vitro induced a temporary down-regulation of CD3 expression at the cell surface. TCR molecules were also affected. Other anti-CD90 Abs not inhibitory to CD4 T cell activation failed to induce a reduction in CD3. Experiments in vitro revealed that the down-regulation caused by LP5 is due to an accelerated endocytosis of cell surface CD3. In addition, it was shown that CD3 down-regulation before or in the early stages of T cell activation is critical for the induction of hyporesponsiveness. Experiments in vivo showed that pre-treatment of CD4 T cells with LP5 inhibited the rejection of semi-allogeneic bone marrow transplants. Based on these observations, we propose that CD3 down-regulation without any stimulatory activity against T cells could be one approach to inhibiting T cell activation, and CD90 would be an appropriate target.
Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, Japan.
Emi
E
Nishida
Chen
C
Chen
Akimichi
A
Morita
Jun
J
Shimizu
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D051381:Rats; D017208:Rats, Wistar; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D018800:Thy-1 Antigens / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D018800:Thy-1 Antigens