The Src-protein tyrosine kinase Lck is required for IL-1-mediated costimulatory signaling in Th2 cells

Src-protein tyrosine kinases are intimately involved in TCR-initiated signa ling in T lymphocytes. One member of this family, Lek, is also involved in CD28-mediated costimulation in Th1 cells. In Th2 lymphocytes, the costimula tory signal can also be provided by the interaction of IL-1 with type I IL- 1R (IL-IRI), culminating in the activation of NF-kappaB transcription facto rs. Proximal steps in the IL-1R pathway, however, remain poorly understood, and there is conflicting evidence as to the importance of tyrosine phospho rylation in IL-1R signaling. We have addressed this issue by examining the ability of IL-1 to costimulate the activation of Lek-deficient Th2 cells. O ur data demonstrate that, in the absence of Lck, the IL-1 costimulatory pat hway is blocked despite the expression of normal levels of IL-1RI. Moreover , the block is associated with a defective degradation of I kappaB-alpha an d an incomplete activation of NF-kappaB heterodimeric complexes. Protein ex pression of NF-kappaB monomers, including p50, p65, and c-Rel, is equivalen t in both wild-type and Lck-deficient Th2 cell clones. Finally, we demonstr ate that, in normal Th2 cells, stimulation with IL-1 leads to a rapid induc tion in tyrosine phosphorylation of several substrates including Lek itself . These findings strongly suggest that Lek is required for signaling in the IL-1 costimulatory pathway in Th2 lymphocytes.