TYROSINE KINASE-ACTIVITY OF CD4-ASSOCIATED P56(LCK) MAY NOT BE REQUIRED FOR CD4-DEPENDENT T-CELL ACTIVATION

The lymphoid-specific tyrosine kinase p56lck (Lck) is critical for the development and activation of T lymphocytes, and Lck kinase activity has been implicated in both T-cell antigen receptor/CD3- and CD4-media ted signaling. CD4-dependent T-cell activation has been demonstrated t o be dependent upon the association of CD4 with Lck. To examine the ro le of the kinase activity of Lck in CD4-dependent T-cell activation, w e have generated several kinase-deficient mutants of Lck. When transfe cted into CD4+ murine T-cell hybridoma cells, these mutants cause almo st-equal-to 90% diminution in CD4-associated Lck kinase activity. Spec ifically, upon CD4 crosslinking there is decreased Lck autophosphoryla tion and decreased phosphorylation of an exogenous substrate. When CD4 is crosslinked to the T-cell antigen receptor-CD3 complex, decreased phosphorylation of associated substrates is also observed. In spite of this striking inhibition of Lck kinase function, cells expressing the kinase-deficient mutants demonstrate normal or enhanced CD4-dependent antigen responsiveness. These data demonstrate that the level of Lck kinase activity does not correlate with its CD4-associated function an d suggest that the kinase activity of Lck may not be required for CD4- mediated signaling.