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Enrichment of Lck in Lipid Rafts Regulates Colocalized Fyn Activation and the Initiation of Proximal Signals through TCR¹

Dominik Filipp^*, Bernadine L. Leung^*, Jenny Zhang^*, André Veillette and Michael Julius^2,*

^* Sunnybrook and Women’s College Health Sciences Center and Department of Immunology, University of Toronto, Toronto, Ontario, Canada; and Laboratory of Molecular Oncology, Institut de Recherches Cliniques de Montreal, and Departments of Microbiology and Immunology and Medicine, McGill University, Montréal, Québec, Canada

Recent results provide insight into the temporal and spatial relationship governing lck-dependent fyn activation and demonstrate TCR/CD4-induced activation and translocation of lck into lipid rafts and the ensuing activation of colocalized fyn. The prediction follows that directly targeting lck to lipid rafts will bypass the requirement for juxtaposing TCR and CD4-lck, and rescue cellular activation mediated by Ab specific for the constant region of TCR chain. The present study uses a family of murine IL-2-dependent CD4⁺ T cell clonal variants in which anti-TCRC signaling is impaired in an lck-dependent fashion. Importantly, these variants respond to Ag- and mAb-mediated TCR-CD4 coaggregation, both of which enable the coordinated interaction of CD4-associated lck with the TCR/CD3 complex. We have previously demonstrated that anti-TCRC responsiveness in this system correlates with the presence of kinase-active, membrane-associated lck and preformed hypophosphorylated TCR:-associated protein of 70 kDa complexes, a phenotype recapitulated in primary resting CD4⁺ T cells. We show in this study that forced expression of wild-type lck achieved the same basal composition of the TCR/CD3 complex and yet did not rescue anti-TCRC signaling. In contrast, forced expression of C20S/C23S-mutated lck (double-cysteine lck), unable to bind CD4, rescues anti-TCRC proximal signaling and cellular growth. Double-cysteine lck targets lipid rafts, colocalizes with >98% of cellular fyn, and results in a 7-fold increase in basal fyn kinase activity. Coaggregation of CD4 and TCR achieves the same outcome. These results underscore the critical role of lipid rafts in spatially coordinating the interaction between lck and fyn that predicates proximal TCR/CD3 signaling.

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