T-CELL ANTIGEN RECEPTOR-INDUCED IL-2 PRODUCTION AND APOPTOSIS HAVE DIFFERENT REQUIREMENTS FOR LCK ACTIVITIES

The T cell hybridoma BI-141 has been previously used to dissect the ro les of Lck in Ag-induced IL-2 production, Here we demonstrate that BI- 141 undergoes apoptosis in response to TCR stimulation using Ag or ant i-TCR Abs. Using a panel of BI-141 transfectants expressing constituti vely activated Lck (F505) or phosphotyrosine-binding (K154F505 and C15 6F505) or kinase-impaired (R273F505) mutants, we assess the relative r equirements for Lck in TCR-mediated IL-2 production and apoptosis, Whi le BI-141 transfectants expressing F505 are dramatically enhanced in t heir ability to produce IL-2 in response to Ag relative to K154F505-, C156F505-, or R273F505-expressing transfectants, no differences betwee n these transfectants are observed in their ability to undergo TCR-ind uced apoptosis, TCR-induced Fas ligand (Fast) expression is demonstrat ed to be dependent on Lck SH2 and kinase activities, although Fast exp ression cannot be correlated with apoptosis, Low levels of Fas are con stitutively expressed at equal levels on transfectants and are not inc reased in response to TCR ligation, Together, these data indicate that TCR-induced apoptosis in BI-141 is regulated through a mechanism(s) d istinct from the Lck-induced expression of Fas, Fast, or IL-2 producti on, This TCR signal may be independent of Lck kinase and SH2 activitie s, or may require lower threshold activity, The identification of diff erential requirements for particular T cell functions is crucial to un derstanding how TCR engagement affects downstream T cell functions and may aid in the rational design of therapeutics aimed at specifically modulating particular T cell responses.