| Anti-CD3 monoclonal antibodies (mAbs) are potent immunosuppressive agents used in clinical transplantation. However, the activation related adverse side effects associated with these mAbs have prompted the development of less toxic Fc receptor (FcR) non-binding anti-CD3 mAb therapy. In this dissertation, the biochemical and functional consequences of FcR non-binding anti-CD3 treatment for various T helper cell populations were examined. The proximal signal delivered by FcR non-binding anti-CD3 resembled an altered peptide ligand signal, in that the mAb was ineffective at inducing the highly phosphorylated form of {dollar}zeta{dollar} and tyrosine phosphorylation of the associated ZAP-70 kinase. Reconstitution of these early signaling events by a bispecific anti-CD3 x anti-CD4 F(ab){dollar}spprimesb2{dollar} suggested that defective association of lck with the T cell receptor (TCR) may underlie the signaling defects observed in the absence of FcR-mediated cross-linking. Downstream of these proximal events, FcR non-binding anti-CD3 induced suboptimal Phospholipase C{dollar}gamma{dollar}-1 and MAPkinase activation. However, NF-AT translocated into the nucleus of T cells stimulated with the mAb. The functional consequences of these partial TCR signals varied among different T helper cell subsets. Although the FcR non-binding anti-CD3 was non-mitogenic for both naive T cells and Th1 cells, the mAb preferentially induced functional anergy in the Th1 subset. In contrast, FcR non-binding anti-CD3 treated Th2 cells secreted IL-4, proliferated, and were not rendered unresponsive. Mixed "Th0" populations responded to FcR non-binding anti-CD3 by producing IL-4, and showed a selective decrease in IL-2 production following pre-culture with the mAb. Together, these results suggest that the mechanism by which FcR non-binding anti-CD3 mAbs suppress immune responses involves the delivery of a partial TCR signal that inactivates Th1 cells and induces cytokine deviation. Thus, FcR non-binding anti-CD3 mAbs may be useful clinically as a non-toxic therapy for Th1 mediated transplant rejection and autoimmune disease. These results also have more general implications for TCR related mechanisms of tolerance induction. |
