We recently discovered that a single nucleotide polymorphism in the human lymphoid tyrosine phosphatase LYP (encoded by the PTPN22 gene) is associated with type 1 diabetes, an autoimmune disease that arises from T lymphocyte-mediated destruction of insulin-producing B-cells in the pancreas (Nature Genetics 36, 337-338). LYP is expressed only in white blood cells and acts as a gatekeeper of T lymphocyte activation. The molecular mechanism by which LYP tempers T lymphocyte activation involves the formation of a complex between LYP and the negative regulatory kinase Csk. We have found that the autoimmune- disposing LYP variant, LYP-W620, cannot bind to Csk and our new preliminary data show that LYP-W620 regulates TCR signaling in a different way than the more common LYP-R620. We hypothesize that LYP genetic polymorphism alters the threshold of T cell activation, thereby predisposing carriers to a misdirected immune response against autoantigens in pancreatic islets or other tissues. In this proposal we wish to generate mouse models carrying T cell-specific expression of the 2 genetic variants of the phosphatase and perform their phenotypic analysis. This will allow us to gain important insights about the effect of the polymorphism on TCR signaling, T cell development and differentiation, and the mechanism of association between the R620W polymorphism and type 1 diabetes. The new mouse models will then be available for further immunological analyses and for studies aimed at validating new pharmacologic approaches to disease prevention or intervention in carriers of the LYP-W620 variant. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI065643-02
Application #
7230253
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2006-08-01
Project End
2009-06-01
Budget Start
2007-08-01
Budget End
2009-06-01
Support Year
2
Fiscal Year
2007
Total Cost
$259,669
Indirect Cost
Name
University of Southern California
Department
Orthopedics
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Wu, Dennis J; Zhou, Wenbo; Enouz, Sarah et al. (2014) Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. PLoS One 9:e86677