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The Gads (GrpL) Adaptor Protein Regulates T Cell Homeostasis¹

Thomas M. Yankee^*, Theodore J. Yun^*,, Kevin E. Draves^*, Kolumam Ganesh, Michael J. Bevan^,, Kaja Murali-Krishna^, and Edward A. Clark^2,*,,

Departments of ^* Microbiology and Immunology, Howard Hughes Medical Institute, and National Primate Research Center, University of Washington, Seattle, WA 98195

Little is known about the role of the Gads (GrpL) adaptor protein in mature T cell populations. In this study we show that the effects of Gads deficiency on murine CD4⁺ and CD8⁺ T cells are markedly different. Gads^–/– CD4⁺ T cells were markedly deficient in the spleen and had an activated phenotype and a rapid turnover rate. When transferred into a wild-type host, Gads^–/– CD4⁺ T cells continued to proliferate at a higher rate than wild-type CD4⁺ T cells, demonstrating a defect in homeostatic proliferation. Gads^–/– CD8⁺ T cells had a memory-like phenotype, produced IFN- in response to ex vivo stimulation, and underwent normal homeostatic proliferation in wild-type hosts. Gads^–/– T cells had defective TCR-mediated calcium responses, but had normal activation of ERK. Gads^–/– CD4⁺ T cells, but not CD8⁺ T cells, had a severe block of TCR-mediated proliferation and a high rate of spontaneous cell death and were highly susceptible to CD95-induced apoptosis. This suggests that the rapid turnover of Gads^–/– CD4⁺ T cells is due to a defect in cell survival. The intracellular signaling pathways that regulate homeostasis in CD4⁺ and CD8⁺ T cells are clearly different, and the Gads adaptor protein is critical for homeostasis of CD4⁺ T cells.

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