SIGNALS THROUGH CD8 OR CD4 CAN INDUCE COMMITMENT TO THE CD4 LINEAGE IN THE THYMUS

Differentiation of thymocytes into mature single-positive T cells is a n ordered process involving sequential interactions between T cell rec eptor (TCR), co-receptors (CD4 or CD8) and their appropriate major his tocompatibility complex-encoded ligands. Precisely how these receptor/ co-receptor engagements determine lineage commitment is still controve rsial, but recently it has been suggested that quantitative difference s in the signal transmitted by co-ligation of CD4 versus CD8 with TCR might provide the discriminating signal. We examine this hypothesis, u sing bispecific F(ab')(2) antibodies to mimic TCR/co-receptor engageme nt during thymocyte differentiation. These bispecific antibodies lack Fc and can engage surface molecules without extensive cross-linking or targeting to Fc receptor-bearing cells. We show that TCR/CD3 co-ligat ion with CD4 induces efficient differentiation of mature CD4 lineage c ells, irrespective of their TCR specificity. Interestingly, TCR/CD3 co -ligation with CD8 also induces maturation of CD4 T cells, although le ss efficiently, but not of CD8 T cells. Thus, although the signals del ivered by co-ligation of TCR and CD8 appear weaker than from co-ligati on of TCR and CD4, the outcome from either engagement is the same. The se data suggest that differences in signal intensity alone do not dete rmine lineage commitment in the thymus, but that distinct signals are required for CD4 and CD8 single-positive cell differentiation.