INFLUENCE OF MHC CLASS-I MOLECULES ON T-CELL PROLIFERATION INDUCED BYCD3 OR THY-1 STIMULATION

We have reported that class I- [and lymphocyte function-associated ant igen-1 (LFA-1-)] specific monoclonal antibodies (mAb) inhibit anti-CD3 -mediated activation of naive T cells. The present study investigated the mechanism of this inhibition. CD28-specific mAb augmented stimulat ion induced by soluble CD3 mAb, but this costimulation was also inhibi ted by anti-class I or anti-LFA-1 mAb. However, stimulation of T cells was not inhibited when activated B cells were present. Neither B7-1- nor B7-2-specific blocking mAb or soluble CTLA-4, CD40 or gp39 restore d the inhibition. Thus, other molecules expressed on activated B cells are implicated for T-cell activation, which could compensate blockade of class I or LFA-1 molecules. Inhibition induced by class I-specific mAb could potentially be mediated through extracellular, transmembran e or cytoplasmic domains of the target molecules. These possibilities were evaluated by the use of mice transgenic for the Qa-2 molecule, se lected for expression of Qa-2 at levels equivalent to classical class I molecules. Qa-2 is inserted in the membrane through phosphatidylinos itol linkages. Antibodies directed to Qa-2 inhibited CD3-induced stimu lation, demonstrating that cytoplasmic and transmembrane protein seque nces of class I molecules are not necessary for the inhibitory effect. Inhibition thus presumably depends on extracellular domains. Finally, T cells from beta 2-microglobulin knock-out mice responded to CD3-spe cific mAb as well as their class I-positive littermates. Nevertheless, stimulation of T cells from these mice with mitogenic anti-Thy-1 mAb was markedly reduced. Signalling by Thy-1 and the CD3 complex may norm ally occur through pathways in which class I molecules are implicated.