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Identification of Tyrosine Phosphorylation Sites in the CD28 Cytoplasmic Domain and Their Role in the Costimulation of Jurkat T Cells¹

Department of Medicine, Rosalind Russell Research Laboratory, San Francisco General Hospital, and University of California, San Francisco, CA 94143

The cytoplasmic domain of CD28 contains four tyrosine residues. Because signal transduction by CD28 appears to involve its tyrosine phosphorylation, we determined sites of CD28 tyrosine phosphorylation using mutants of mouse CD28 that retained tyrosine at one position, with the remaining three positions mutated to phenylalanine. When expressed in Jurkat cells and stimulated by mAb, only the mutants with tyrosine at position 170 or 188 were tyrosine phosphorylated. Phosphorylation of Tyr¹⁷⁰ recruits phosphatidylinositol 3-kinase to CD28. Tyr¹⁸⁸ has not been associated with any specific signaling event, but we found that ligation of CD28 by the natural ligand B7.2 also induced phosphorylation of Tyr¹⁸⁸, suggesting that this event is of physiological importance. Consistent with that possibility, mutation of Tyr¹⁸⁸ to phenylalanine severely impaired the ability of mouse CD28 to deliver a costimulus for the expression of CD69 and the production of IL-2. The functional consequences of the mutation of Tyr¹⁸⁸ were unique; mutation of the other three tyrosines, individually or in combination, did not impair costimulation. Therefore, of the four CD28 tyrosine residues only Tyr¹⁸⁸ is required for signaling in Jurkat cells, suggesting that its phosphorylation is a key event in the costimulation of T cells.

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