The Role of LAT-PLCγ1 Interaction in γδ T Cell Development and Homeostasis

LAT is a transmembrane adaptor protein that is vital for integrating TCR-mediated signals to modulate T cell development, activation, and proliferation. Upon T cell activation, LAT is phosphorylated and associates with Grb2, Gads, and PLC gamma 1 through its four distal tyrosine residues. Mutation of one of these tyrosines, Y136, abolishes LAT binding to PLC gamma 1. This results in impaired TCR-mediated calcium mobilization and Erk activation. CD4 alpha beta T cells in LATY136F knock-in mice undergo uncontrolled expansion, resulting in a severe autoimmune syndrome. In this study, we investigated the importance of the LAT-PLC gamma 1 interaction in gamma delta T cells by crossing LATY136F mice with TCR beta(-/-) mice. Our data showed that the LATY136F mutation had no major effect on homeostasis of epithelial gamma delta T cells, which could be found in the skin and small intestine. Interestingly, a population of CD4(+) gamma delta T cells in the spleen and lymph nodes underwent continuous expansion and produced elevated amounts of IL-4, resulting in an autoimmune syndrome similar to that caused by alpha beta T cells in LATY136F mice. Development of these hyperproliferative gamma delta T cells was not dependent on MHC class II expression or CD4, and their proliferation could be suppressed, in part, by regulatory T cells. Our data indicated that a unique subset of CD4 gamma delta T cells can hyperproliferate in LATY136F mice and suggested that LAT-PLC gamma 1 signaling may function differently in various subsets of gamma delta T cells.