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-Independent CD28 Signaling and Costimulation Require Non-CD4-Associated Lck1
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Department of Immunology, University of Toronto, and Arthritis and Immune Disorder Research Centre, Toronto, Ontario, Canada;
McGill Cancer Centre, Departments of Biochemistry, Medicine, and Oncology, McGill University, Montreal, Quebec, Canada;
Oncology Gene Therapy Program, The Toronto Hospital, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and
Ontario Cancer Institute, Toronto, Ontario, Canada
Whether the sequelae of signals generated through CD28 either directly or in circumstances of costimulation require proximal events mediated by p56lck remains contentious. We demonstrate that CD4-, but not CD4+ clonal variants respond to CD28-specific mAb with both early and late indicators of activation. Forced expression of A418/A420-mutated CD4 or wild-type CD4 in the CD4- variant recapitulated the CD28-mediated responses of the CD4- and CD4+ variants, respectively. The implicated involvement of non-CD4-associated Lck is formally demonstrated by overexpressing S20/S23 Lck or wild-type Lck in CD4+ variants. The former, but not latter, rescues direct CD28 signaling, and supports costimulation. The results demonstrate that constitutive levels of non-CD4-associated Lck functionally limit CD28-mediated signaling.
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