Linker for activation of T cells (LAT) in the regulation of T cell activation and autoimmunity (BA2P.121)

Abstract

Abstract The transmembrane adaptor protein LAT (Linker for Activation of T cells) is essential in T cell development, activation, survival, and homeostasis. Upon T cell activation, it is tyrosine phosphorylated and interacts with many signaling proteins, such as Grb2, Gads, and PLC-γ1. The mutation of tyrosine 136 on LAT abrogates its interaction with PLC-γ1, causing defective TCR-mediated signaling. Mice harboring this mutation, LATY136F, have significantly impaired thymocyte development; however, they rapidly develop a severe lymphoproliferative disease marked by the uncontrolled expansion of Th2-skewed CD4+ T cells, high levels of IgE and IgG1, and autoantibody production. In this study, we assessed the contribution of multiple signaling pathways in this disease using mice deficient in Gads and RasGRP1 and mice with constitutive activation of the NFAT and NF-κB pathways. We also examined the role of MHC and CD4 in the development of these pathogenic T cells and further investigated how T follicular helper cells and cytokines contribute to LAT-mediated autoimmunity.