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

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.

Large Granular Lymphocytic Leukemia: Clinical Features, Molecular Pathogenesis, Diagnosis and Treatment

“…LGLs persist [49]. There is abnormal regulation of LGL leukemic cells through the pathways involved in activation-induced cell death (AICD), leading to expanded effector memory cytotoxic T cell population by chronic persistent antigen exposure that then leads to the STAT3 activation mutation, which is seen in 30-40% of patients [9,10,49].…”

“…LGLs are activated through antigen recognition, then undergo significant expansion and eventually death by apoptosis after antigen clearance. In LGL leukemia, however, these LGLs persist [49]. There is abnormal regulation of LGL leukemic cells through the pathways involved in activation-induced cell death (AICD), leading to expanded effector memory cytotoxic T cell population by chronic persistent antigen exposure that then leads to the STAT3 activation mutation, which is seen in 30-40% of patients [9,10,49].…”

“…In LGL leukemia, however, these LGLs persist [49]. There is abnormal regulation of LGL leukemic cells through the pathways involved in activation-induced cell death (AICD), leading to expanded effector memory cytotoxic T cell population by chronic persistent antigen exposure that then leads to the STAT3 activation mutation, which is seen in 30-40% of patients [9,10,49]. The following sections describe the molecular pathogenesis of LGL leukemia, and a summary of the pathways reported in the literature [15,50,51] is shown in Figure 1.…”