Impaired T cell tolerance is the cause of all types of autoimmune diseases, which suffers more than 23 million Americans. Since Sir Frank Macfarlane Burnet first described immune tolerance in late 1950s and received the 1960 Nobel Prize in Physiology or Medicine, tremendous efforts have identified genes that are responsible for T cell tolerance, the molecular mechanisms in particularly underlying the peripheral T cell tolerance remain an immunological mystery. The current dogma is that TCRs on self-reactive T cells, upon recognition of self-antigens without CD28 co-stimulation, mediate the activation of NFAT to promote the expression of genes that suppress the activation of self-reactive T cells (known as anergic genes). However, additional factors yet to be identified to fully explain the molecular puzzles of T cell tolerance. We speculate that, in addition to upregulating the suppressive genes, anergic signaling may down-regulate certain activators (positive regulators) of T cells to induce and maintain the peripheral tolerance. By comparing the gene expression profiles of anergic T cells with na?ve and activated T cells, we demonstrated that downregulation of Synoviolin expression leads to T cell tolerance. We then generated T cell-specific Synoviolin knockout mice. Using this unique mouse model, we demonstrated that genetic deletion of Synoviolin gene promotes T cell tolerance induction, inhibits T cell activation and protects mice from autoimmune disease, implying Synoviolin as a potential therapeutic target for autoimmune diseases. The current study is to illuminate the molecular mechanisms of Synoviolin in T cell tolerance and activation. We will also use both the genetic and pharmacological approaches to evaluate the efficacy of Synoviolin suppression in autoimmune treatment in mice.

Public Health Relevance

Our studies here will identify Synoviolin as a novel regulator of T cell immunity during autoimmune diseases. We will discover that Synoviolin suppression is a new therapeutic approach in the treatment of autoimmune inflammatory diseases and to achieve an optimal immune suppression to prolong the graft survival in organ transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI108634-01A1
Application #
8756545
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Esch, Thomas R
Project Start
2014-07-11
Project End
2018-06-30
Budget Start
2014-07-11
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$379,464
Indirect Cost
$129,464
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kong, Sinyi; Thiruppathi, Muthusamy; Qiu, Quan et al. (2014) DBC1 is a suppressor of B cell activation by negatively regulating alternative NF-?B transcriptional activity. J Immunol 193:5515-24