CD2 and CD3 receptor-mediated tolerance - Constraints on T cell activation

Background. Antigen specific allograft tolerance is induced in mice by anti -CDS plus anti-CD3 epsilon monoclonal antibody (mAb) treatment. Because ant i-CD2 mAb inhibits several aspects of anti-CD3 epsilon driven T cell activa tion, we investigated what components of T cell activation are required or may be dispensed with for tolerance induction. Anti-CD3 epsilon-mediated T cell activation depends on Fc gamma R interactions. Methods. To assess the role of Fc gamma R-mediated T cell activation in tol erance induction, Fc gamma R binding IgG or non-binding IgG(3) anti-CD3 eps ilon mAbs were examined. Results. These mAbs, administered in conjunction with anti-CD2, were equall y effective in inducing tolerance, Moreover, in vivo administration of a bl ocking mAb directed against the Fc gamma R, or the use of allograft recipie nts deficient in Fc gamma R, had no effect on tolerance induction. Blocking IL-2 using mAb directed against IL-2 or IL-2R also did not prevent the ind uction of tolerance. These results suggest that complete T cell activation was not required for tolerance induction, However, substitution of a partia lly activating mAb, directed against the T cell receptor (TCR) beta subunit for anti-CD3 epsilon, failed to synergize with anti-CD2 mAb to induce tole rance. The anti-TCR beta mAb and anti-CD3 epsilon mAb were found to differe ntially down modulate expression of TCR/CD3 complex subunits, In particular , anti-CD3 epsilon caused transient down modulation of the TCR beta recepto r subunit and the TCR zeta signaling module, and this pattern was enhanced and prolonged by anti-CD2. Anti-TCR beta caused persistent TCR zeta modulat ion but no TCR beta modulation, and anti-CD2 did not influence this pattern . Conclusions. These results suggest that, although full T cell activation is not required for the induction of tolerance by anti-CD2 plus anti-CD3 epsi lon mAb, a signal transduction pathway that is associated with TCR beta and TCR zeta expression, and, specifically, is perturbed by mAb binding of the CD3 epsilon epitope, is critical.