Evidence for a dual pathway of activation in CD43-stimulated Th2 cells: differential requirement for the Lck tyrosine kinase.

CD43 is the most abundant cell surface-expressed sialoglycoprotein on T lymphocytes. Despite evidence demonstrating the activation of some signaling components by CD43, the exact function of CD43 in T cell biology remains controversial. In this study, we demonstrate that the sole ligation of CD43 in cloned Th2 cells resulted in cytokine production, cellular proliferation, and upregulation of CD25 and CD69 activation markers. Similarly, cross-linking of CD43 on naive splenic T cells led to a significant proliferative response and an enhancement of the expression of CD25 and CD69 markers. These responses required no additional signals from other T cell molecules, including TCR. In Lck-deficient Th2 cells, however, CD43 ligation led to IL-4 production and an increase in the expression of CD25 and CD69 antigens but, surprisingly, no proliferation. Analysis of signaling pathway components revealed that CD43 associates with the adaptor protein SLP-76 within 30 s of activation. This induces the tyrosine phosphorylation of SLP-76 and promotes the recruitment and phosphorylation of another adaptor, Shc. The formation of this multi-component complex was strictly dependent on Lck. In contrast, comparison of tyrosine phosphorylated proteins in whole extracts of normal and Lck-deficient cells revealed a strikingly similar pattern of phosphorylation involving two major protein bands at 26 and 78 kDa. This suggests that tyrosine kinases other than Lck are activated by CD43 ligation. Taken together, the data support the notion that CD43 ligation may induce a dual pathway leading to the activation of different effector functions in Th2 lymphocytes.