Recognition of MHC-peptide complexes by the TCR activates Src and Syk family tyrosine kinases and induces phosphorylation of signaling proteins. One of the prominently phosphorylated proteins is LAT (linker for activation of T cells). LAT is a palmitoylated transmembrane adaptor protein that binds Grb2, Gads, PLC- y1, and other signaling molecules, thus recruiting these molecules to the plasma membrane to activate downstream signaling events, such as Ras-MAPK activation and Ca2+ flux. Previous studies with LAT- deficient Jurkat cells demonstrate that LAT is essential for TCP-mediated signal transduction and LAT palmitoylation is required for LAT phosphorylation and function. LAT-deficient mice have an early block in thymocyte development. Recent studies show that LAT also plays an important role in T cell homeostasis. Mice that express a LAT mutant that fails to bind PLC-y1 develop a severe autoimmune disease. Based on current information and our preliminary findings, we propose that, by coupling TCR engagement to Ras- MAPK activation and Ca2+ flux, LAT plays an important role in regulating T cell activation, survival, and homeostasis. There are three specific aims designed to test this hypothesis and to further understand how LAT functions in T cells.
In specific aim 1, we will use mice, in which the Lat gene can be deleted by the Cre recombinase, to study the role of LAT during thymocyte development.
In specific aim 2, we will induce deletion of the Lat gene in vivo and in vitro to study LAT function in mature T cells. We will focus on the role of LAT and the LAT-PLCy! interaction in TCR-mediated signaling, T cell activation, homeostatic proliferation, and cell survival.
In specific aim 3, we will use LAT conditional knockout mice to study whether normal LAT function is required for Treg cell survival in the periphery. We will also investigate the role of the Ca2+ pathway in Treg cell development and autoimmunity using mice that express a constitutively active form of calcineurin. T cells are the central components of our immune system. LAT is one of the molecules that play essential roles in T cell activation. Determination of LAT function and further understanding TCR signaling pathway could facilitate the design of a rational approach to augment or inhibit T cell proliferation in autoimmunity, allergy, and tissue and organ transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048674-09
Application #
7727358
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Mallia, Conrad M
Project Start
2001-01-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
9
Fiscal Year
2010
Total Cost
$449,695
Indirect Cost
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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O'Brien, Sarah A; Zhu, Minghua; Zhang, Weiguo (2015) The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity. J Immunol 195:695-705
Sullivan, Sarah A; Zhu, Minghua; Bao, Steven et al. (2014) The role of LAT-PLC?1 interaction in ?? T cell development and homeostasis. J Immunol 192:2865-74
Wu, Xiaomei; Wu, Fei-Hua; Wang, Xiaoqiang et al. (2014) Molecular evolutionary and structural analysis of the cytosolic DNA sensor cGAS and STING. Nucleic Acids Res 42:8243-57
Ou-Yang, Chih-wen; Zhu, Minghua; Sullivan, Sarah A et al. (2013) The requirement of linker for activation of T cells in the primary and memory responses of CD8 T cells. J Immunol 190:2938-47
Zhu, Minghua; Fuller, Deirdre M; Ou-Yang, Chih-wen et al. (2012) Tyrosine phosphorylation-independent regulation of lipopolysaccharide-mediated response by the transmembrane adaptor protein LAB. J Immunol 188:2733-41
Fuller, Deirdre M; Zhu, Minghua; Song, Xiaohua et al. (2012) Regulation of RasGRP1 function in T cell development and activation by its unique tail domain. PLoS One 7:e38796
Zhu, Minghua; Fuller, Deirdre M; Zhang, Weiguo (2012) The role of Ras guanine nucleotide releasing protein 4 in Fc epsilonRI-mediated signaling, mast cell function, and T cell development. J Biol Chem 287:8135-43
Ou-Yang, Chih-wen; Zhu, Minghua; Fuller, Deirdre M et al. (2012) Role of LAT in the granule-mediated cytotoxicity of CD8 T cells. Mol Cell Biol 32:2674-84
Fuller, Deirdre M; Zhu, Minghua; Koonpaew, Surapong et al. (2012) The importance of the Erk pathway in the development of linker for activation of T cells-mediated autoimmunity. J Immunol 189:4005-13

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