The roles of Synoviolin in immune tolerance and autoimmunity

Project: Research project

Project Details


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 naïve 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.
Effective start/end date7/11/146/30/19


  • National Institute of Allergy and Infectious Diseases (5R01AI108634-04)


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