TCR CD3 COUPLING TO FAS-BASED CYTOTOXICITY

We studied the coupling of the TCR/CD3 complex to a T cell effector fu nction, namely Fas-based T cell-mediated cytotoxicity. Encounter or re -encounter with antigen was mimicked by treating 5 d mixed lymphocyte culture cells or T cell hybridomas with anti-CD3 antibody. This TCR/CD S engagement induced swift expression of Fas-based cytotoxicity in the se cells. Induction of Fas-based cytotoxicity was Ca2+-dependent, whil e its execution was not; induction was sensitive to macromolecular syn thesis inhibitors, in line with a demonstrable increase of the Fas lig and (Fas-L) message. We also used T cell hybridomas transfected with v arious constructs to dissect the involvement of distinct components of the TCR/CD3 complex. The cytoplasmic domain of the CD3 zeta chain was able to transduce by itself a signal leading to Fas-L expression, unl ess there were mutations in its activation receptor homology sequence 1 (ARH-1) motifs. On the one hand, these findings are relevant to sign al transduction pathways coupled to the TCR/CD3, and on the other hand , to the involvement of Fas-based T cell-mediated cytotoxicity in vari ous physiological and possibly pathophysiological situations.