Th2 specific immunity and function of peripheral T cells requires the p56Lck SH3 domain (84.15)

Abstract

Abstract T-cell activation and effector function is essential for immunity. T-cell antigen receptor (TCR) signals can regulate the outcome of differentiation, but the mechanisms are unclear. We have found that the Src family tyrosine kinase, p56Lck, specifically links TCR signals to activation of the Mitogen Protein Kinase (MAPK) pathway through the action of its SH3 domain and controls T cell activation and Th2 immunity. We have utilized an Lck SH3 mutant knock-in mouse line, LckW97A, to investigate the potential role of this regulatory domain in regulation of T-lymphocyte activation and effector function. Our results demonstrate that the p56Lck SH3 domain is required for normal activation of T-lymphocytes. LckW97A T-cells have reduced IL-2 production, CD69 induction and proliferation following TCR stimulation. Biochemical studies show that activation of the MAPK pathway is selectively altered as P-ERK1/2 induction is significantly reduced but phospho-PLCγ1 induction is unaffected. In vivo experiments demonstrate significantly impaired Th2 immunity with reduced serum levels of IgG1, IgE and IL-4 following immunization with DNP-KLH or infection with the helminth Nippostrongylus brasiliensis. These data indicate that p56Lck SH3 domain regulates activation of T-lymphocytes by controlling MAPK pathway induction and demonstrate a critical role for p56Lck in the regulation of Th2-type immunity.