Dok-1 and Dok-2 Regulate the Formation of Memory CD8+ T Cells.

Diverse signals received by CD8(+) T cells are integrated to achieve the required magnitude of cell expansion and the appropriate balance of effector/memory CD8(+) T cell generation. Notably, the strength and nature of TCR signaling influence the differentiation and functional capacity of effector and memory CD8(+) T cells. Dok-1 and Dok-2, the two members of the Dok family expressed in T cells, negatively regulate TCR signaling in vitro. However, the role of Dok proteins in modulating T cell function in vivo has not yet studied. We studied the function of Dok-1 and Dok-2 proteins in the regulation of the CD8(+) T cell response to vaccinia virus infection. Comparison of responses to vaccinia virus expressing OVA peptide SIINFEKL by wild-type and Dok-1/2(-/-) CD8(+) OT-I cells showed that the absence of Dok-1 and Dok-2 slightly reduced the magnitude of virus-specific effector CD8(+) T cell expansion. This was not due to reduced proliferation or enhanced apoptosis of effector CD8(+) T cells. Dok-1/2-deficient effector CD8(+) T cells showed increased cell surface TCR expression following virus infection in vivo and increased expression of granzyme B and TNF upon stimulation with peptide Ag ex vivo. Finally, Dok-1/2-deficient effector CD8(+) T had a severe defect in survival that resulted in impaired generation of memory CD8(+) T cells. These results reveal the critical involvement of Dok-1 and Dok-2 in a negative-feedback loop that prevents overactivation of CD8(+) T cells and promotes memory formation.

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