LIGATION OF THE V7 MOLECULE ON T-CELLS BLOCKS ANERGY INDUCTION THROUGH A CD28-INDEPENDENT MECHANISM

Previous studies have demonstrated that a mAb that recognizes the leuk ocyte surface Ag V7 inhibits TCR/CD3-dependent T cell activation, In t he current study, we demonstrate that in addition to inhibiting T cell proliferation and IL-2 production, anti-V7 blocks tyrosine phosphoryl ation of TCR/CD3-associated substrates, PMA overcomes this effect, and both PMA and exogenous IL-2 overcome anti-V7-mediated inhibition of T cell proliferation and IL-2 production, T cells stimulated with anti- CD3 in the absence of CD28 or V7 ligation become unresponsive (anergic ) to restimulation with anti-CD3; T cells primed in the presence of ei ther anti-V7 or anti-CD28 retain their ability to respond to restimula tion with anti-CD3, When T cells are primed in the presence of optimal concentrations of anti-V7 and anti-CD28 Abs, they proliferate normall y, indicating that the costimulatory signals generated through CD28 do minate the inhibitory signals generated through V7, However, as the an ti-CD28 stimulus is diluted, the V7 effect becomes dominant and prolif eration is inhibited. Thus, although both anti-V7 and anti-CD28 Abs pr event anergy, they induce distinct, competing intracellular signals, W ortmannin, which blocks phosphoinositol 3-kinase-dependent signaling,h as little effect on V7-mediated inhibition, while herbimycin, an inhib itor of tyrosine kinase, synergizes with anti-V7 to inhibit T cell act ivation. On the basis of these findings, V7-mediated signals appear to inhibit TCR-dependent tyrosine kinases that are required for IL-2 pro duction and cellular proliferation.