Gads Regulates the Expansion Phase of CD8+ T Cell-Mediated Immunity

Abstract

The Gads adaptor protein is critical for TCR-mediated Ca2+ mobilization. We investigated the effect of Gads deficiency on the proliferation of CD8+ T cells following peptide stimulation and in the context of infection with an intracellular pathogen. We stimulated CD8+ T cells from Gads+/+ OT-I and Gads−/− OT-I mice with cognate Ag (SIINFEKL) or altered peptide ligand. In vitro experiments revealed that Gads was required for optimal proliferation of CD8+ T cells. This defect was most evident at the early time points of proliferation and when low doses of Ag were used as stimuli. Cell cycle analysis demonstrated that Gads−/− CD8+ T cells had impaired TCR-mediated exit from the G0 phase of the cell cycle. Furthermore, Gads−/− CD8+ T cells had delayed expression of c-myc and CD69 upon the stimulation with SIINFEKL. We then investigated how Gads deficiency would impact CD8+ T cell-mediated immunity in the context of infection with an intracellular pathogen. At early time points, Gads+/+ and Gads−/− CD8+ T cells proliferated to a similar extent, despite the fact that expression of CD69 and CD25 was reduced in the absence of Gads. After 5 d postinfection, Gads was required to sustain the expansion phase of the immune response; the peak response of Gads−/− cells was significantly lower than for Gads+/+ cells. However, Gads was not required for the differentiation of naive CD8+ T cells into memory cells. We conclude that the primary function of Gads is to regulate the sensitivity of the TCR to Ag ligation.