Linker for activation of T cells (LAT) is a palmitoylated transmembrane adaptor protein that is indispensable for signaling through the TCR. Upon TCR engagement, it is phosphorylated on multiple tyrosine residues, allowing it to bind Grb2, Gads, PLC- 1, and other signaling molecules. Published studies have clearly demonstrated that LAT is essential in thymocyte development and T cell activation. Additionally, LAT is critical for T cel homeostasis. Mice expressing the LATY136F mutant, which cannot bind PLC- 1, develop a severe lymphoproliferative disease due to uncontrolled T cell expansion and cytokine production. Moreover, mice with LAT deleted in mature T cells develop a similar disease. While LAT function in TCR-mediated signaling is well understood, how LAT regulates T cell homeostasis, cytokine production, and autoimmunity remains unknown. The three specific aims described here are designed to address this question.
In specific aim 1, we will investigate the role of LAT-mediated tonic signaling in the control of T cell expansion and cytokine production using LAT conditional knockout mice. We will study epigenetic changes at cytokine loci and the effect of LAT mutation on the expression of transcription factors that regulate cytokine production.
In specific aim 2, we will investigate the effect of LAT mutation on cytokine-mediated signaling. We will also examine whether TCR- and cytokine-mediated pathways crosstalk, which previous studies have suggested.
In specific aim 3, we will study the role of LAT function in the development of T cells and why LAT mutation in T cells causes autoimmunity. Completion of these specific aims will enhance our fundamental understanding of TCR-mediated signaling in the regulation of T cell expansion and cytokine production. Furthermore, these studies will provide us with knowledge that is imperative to understand and better treat autoimmune diseases.

Public Health Relevance

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
High Priority, Short Term Project Award (R56)
Project #
2R56AI048674-11
Application #
8534340
Study Section
Special Emphasis Panel (ZRG1-IMM-N (03))
Program Officer
Mallia, Conrad M
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
11
Fiscal Year
2012
Total Cost
$384,995
Indirect Cost
$134,995
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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
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
Markegard, Evan; Trager, Evan; Yang, Chih-wen Ou et al. (2011) Basal LAT-diacylglycerol-RasGRP1 signals in T cells maintain TCR? gene expression. PLoS One 6:e25540
Fuller, Deirdre M; Zhu, Minghua; Ou-Yang, Chih-Wen et al. (2011) A tale of two TRAPs: LAT and LAB in the regulation of lymphocyte development, activation, and autoimmunity. Immunol Res 49:97-108

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