MOLECULAR REQUIREMENTS FOR LINEAGE COMMITMENT IN THE THYMUS - ANTIBODY-MEDIATED RECEPTOR ENGAGEMENTS REVEAL A CENTRAL ROLE FOR LCK IN LINEAGE DECISIONS

Recent experiments in our laboratory have focused on the receptor enga gements required for the differentiation of fully mature, single posit ive thymocytes from their double positive precursors. We have used a n ovel approach which involves the ligation of surface receptors on imma ture thymocytes with genetically engineered F(ab')(2) reagents, which, unlike conventional antibodies, do not aggregate the CD3 complex to s uch an extent as to induce extensive deletion of these cells. The expe rimental data presented in this review indicate that differentiation o f the two mature CD4 and CD8 lineages occurs in response to distinct i ntracellular signals induced by particular receptor engagements. The d ata suggest that the tyrosine kinase p56(lck) (lck) plays a crucial ro le in determining lineage choice, in that maturation of thymocytes int o the CD4 lineage occurs upon recruitment of active lck to the T-cell receptor (TCR)/CD3 complex, whereas CD8 maturation can be induced by C D3 ligation in the absence of co-receptor-mediated lck recruitment. A central role for lck activity in determining the threshold for differe ntiation of the CD4 lineage is revealed in experiments with thymi defi cient for a regulator of lck activity, CD45. A model of thymocyte diff erentiation is presented in which we propose that the relative balance of signals delivered by TCR engagement and lck activation determines lineage choice.