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CD2 and CD3 receptor-mediated tolerance: constraints on T cell activation
J D Punch1, J Lin, J Bluestone
1Department of Surgery, University of Michigan, Ann Arbor 48104, USA.
Background:
Antigen specific allograft tolerance is induced in mice by anti-CD2 plus anti-CD3epsilon monoclonal antibody (mAb) treatment. Because anti-CD2 mAb inhibits several aspects of anti-CD3epsilon driven T cell activation, we investigated what components of T cell activation are required or may be dispensed with for tolerance induction. Anti-CD3epsilon-mediated T cell activation depends on FcgammaR interactions.
Methods:
To assess the role of FcgammaR-mediated T cell activation in tolerance induction, FcgammaR binding IgG or non-binding IgG3 anti-CD3epsilon mAbs were examined.
Results:
These mAbs, administered in conjunction with anti-CD2, were equally effective in inducing tolerance. Moreover, in vivo administration of a blocking mAb directed against the FcgammaR, or the use of allograft recipients deficient in FcgammaR, had no effect on tolerance induction. Blocking IL-2 using mAb directed against IL-2 or IL-2R also did not prevent the induction of tolerance. These results suggest that complete T cell activation was not required for tolerance induction. However, substitution of a partially activating mAb, directed against the T cell receptor (TCR) beta subunit for anti-CD3epsilon, failed to synergize with anti-CD2 mAb to induce tolerance. The anti-TCRbeta mAb and anti-CD3epsilon mAb were found to differentially down modulate expression of TCR/CD3 complex subunits. In particular, anti-CD3epsilon caused transient down modulation of the TCRbeta receptor subunit and the TCRzeta signaling module, and this pattern was enhanced and prolonged by anti-CD2. Anti-TCRbeta caused persistent TCRzeta modulation but no TCRbeta 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-CD3epsilon mAb, a signal transduction pathway that is associated with TCRbeta and TCRzeta expression, and, specifically, is perturbed by mAb binding of the CD3epsilon epitope, is critical.