There is good evidence from murine models such as EAE that T-cells that express a TCR specific for a self-peptide can incite tissue-specific autoimmune disease, usually after deliberate immunization. However, the events that lead to spontaneous activation of these cells are poorly understood. What triggers autoimmune T-cells? How do they induce pathogenic tissue destruction? Are environmental factors such as microbial pathogens involved in this process and how do these T-cells escape intrathymic or peripheral tolerance mechanisms? Once activated, which T-cell cytokines are necessary for disease progression? And can cells and molecules that may down-regulate expansion and differentiation of autoreactive T-cell clones be delineated and thereby diminish autoimmune disease? The investigator proposes studies to continue to define the cellular and molecular events responsible for initiation and progression of the autoimmune disease process that is initiated by HSV-1 (KOS) infection of inbred mice. The investigator has found that this disorder is provoked by a dominant CD4+ T-cell clone that expresses a particular TCR (Valpha11.b Jalpha33; Vbeta8. 1/Dbeta1. 1/Jbeta1.4/Cbeta1). The activity of this pathogenic T-cell clone, termed CI-6, is regulated by two types of TCR:peptide interactions: 1) an interaction with a cross-reactive self-peptide derived from IgG2a b inhibits the response of these cells; 2) an interaction with an HSV-1-derived (UL6) peptide activates these cells. The investigator has constructed mice that express the V alpha11/Vbeta8.1 C1-6 TCR transgene and generated replication-competent UL6 mutant HSV-I (KOS) strains to further define this process. The investigator has also made progress in defining the mechanisms that regulate disease progression. Recognition of autoantigen is necessary but not sufficient for autoimmune disease; expression of particular cytokine genes is necessary for progressive tissue destruction. The investigator has identified a novel T-cell cytokine termed Eta-1 (for Early T-lymphocyte activation-1) that appears to play an essential role in this process and in the provocation of Type 1 immunity. Finally, the investigator's studies of the immunoregulatory interactions that control disease progression have uncovered an important inhibitory role for the class Ib MHC molecule Qa1 and form the basis of an effort intended to delineate the cellular basis of this immunoregulatory effect and establish its therapeutic potential.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunological Sciences Study Section (IMS)
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Wiesch, Denise
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Dana-Farber Cancer Institute
United States
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Shen, Erxia; Wang, Qin; Rabe, Hardis et al. (2018) Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells. Proc Natl Acad Sci U S A 115:6780-6785
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Holderried, Tobias A W; Lang, Philipp A; Kim, Hye-Jung et al. (2013) Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection. Proc Natl Acad Sci U S A 110:21089-94
Kim, Hye-Jung; Wang, Xuan; Radfar, Soroosh et al. (2011) CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc Natl Acad Sci U S A 108:2010-5
Kim, Hye-Jung; Cantor, Harvey (2011) Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells. Semin Immunol 23:446-52
Kim, Hye-Jung; Verbinnen, Bert; Tang, Xiaolei et al. (2010) Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature 467:328-32

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