LAT is a transmembrane adaptor protein that plays an essential role in TCR signaling and T cell activation. Upon TCR engagement, it is phosphorylated on multiple tyrosine residues and binds to Grb2, Gads, and PLC-g1, leading to activation of multiple signaling cascades, such as Ras-MAPK and calcium flux. Patients with LAT mutations develop a lethal autoimmune disease in patients. Despite significantly weakened signaling, their T cells were hyperproliferative, skewed to Th2, and constitutively produced IL-4. These patients had hypergammaglobulinemia and elevated autoantibodies. These symptoms were strikingly very similar to the phenotype of LATY136F mice, in which the LAT PLC-g1 binding site was mutated. Because of the similarity, we will use the LATY136F mice as a model to study what drives T cell expansion and autoimmunity in these patients. Our data suggested that CD4+ T cells could develop and expand in LATY136F mice without MHC. Based on these data, we hypothesize that LAT-mediated signaling imposes MHC restriction on ab T cells and controls the development of autoimmunity. To test this hypothesis, we propose the following specific aims:
In aim #1, we will investigate the role of TCR in T cell hyperproliferation and autoimmunity in LATY136F mice.
In aim #2, we will perform biochemical analysis of signaling pathways downstream of MHC-independent TCR.
In aim #3, we will identify antigens that are recognized by MHC- independent TCRs and characterize their interaction. Completion of these aims will enhance our fundamental understanding of TCR-mediated signaling in the regulation of thymic selection, expansion, and homeostasis. Furthermore, these studies will provide us with knowledge to improve treatment of autoimmune diseases.

Public Health Relevance

T cells are the central components of our immune system. LAT is a signaling molecule that plays an essential role in thymocyte development and T cell activation. We plan to study LAT function in the control of MHC restriction, thymic selection, and development of autoimmunity. The proposed research may have important clinical implications for the treatment of autoimmune patients with mutations in TCR signaling proteins. Our study will have an important and positive impact on human health and provide new targets for the development of therapeutic drugs to augment or to inhibit immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI137756-02
Application #
9620010
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Prabhudas, Mercy R
Project Start
2018-01-03
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Duke University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705