Myocarditis is an inflammation of the heart muscle which often follows microbial infections and evidence indicates that autoimmunity to heart antigens contributes to cardiac injury. Enteroviruses, including coxsackievirus B3 (CVB3), are major etiological agents causing this clinical disease. A mouse model of CVB3 induced myocarditis shares many characteristics of the human disease. Immunity is usually divided into innate (constitutively present or rapidly induced and having either no pathogen specificity or very broad specificity) and adaptive (highly specific responses to inducing pathogen) types. It is clear that the innate immune response can determine both the quality and quantity of the subsequent adaptive immune response. Two innate effectors are: T cells expressing the gamma-delta T cell receptor (34 T cells) and invariant natural killer T (iNKT) cells which express an invariant T cell receptor 1 chain and one of a limited number of 2 TCR chains. In CVB3 induced myocarditis, the V34 subpopulation of 34 T cells is crucial to induction of autoimmunity to cardiac antigens and inflammation in the heart which iNKT cells are protective. Both V34 and iNKT cells react to CD1d, a non-classical major histocompatibility complex class 1-like molecule. CD1d is not only expressed on antigen presenting cells including dendritic cells and macrophage, but is also up-regulated on CD4 T cells in CVB3 infected mice, including a subpopulation of CD4+CD25+FoxP3+ T regulatory cells. Furthermore, the CD1d+ T regulatory cell subpopulation is substantially more immunosuppressive than the CD1d- T regulatory cells from the same infected animal. We provide evidence that 34 T cells in CVB3 infected mice inhibits T regulatory cell responses while iNKT cells promote T regulatory cell response. We hypothesize that 34 T and iNKT cells counter-balance each other and the ultimate ability of CVB3 infected mice to ddevelop autoimmunity and myocarditis depends upon which innate effector dominates. We propose to use two established CVB3 vartiants, H3 and H310A1, which have been cloned and sequenced. H3 virus activates 34 T cells, fails to activate T regulatory cells and induces cardiac autoimmunity. In contrast, H310A1 virus, which differs by a single amino acid from H3 virus, fails to activate 34 T cells, induces T regulatory cells and fails to induce autopimmunity.
The Specific Aims will determine: 1) the mechanism(s) by which 34 T and iNKT cells control T regulatory cell activation and how these two effectors counter-balance each other in impacting developing adaptive immunity;and 2) why H3 and H310A1 differ in ability to activate T regulatory cells.
Myocarditis is an inflammation of the heart muscle which usually follows microbial infections. Disease depends upon activation of pathogenic CD4 T cells and optimal activation of these effectors depends upon a population of 34 T cells which prevent the activation of immunosuppressive T regulatory cells. The studies in this proposal will determine how 34 T cells prevent T regulatory cell activation. The hypothesis is that 34 T cells either interact with dendritic cells through CD1d to change the dendritic cells from a pro-inflammatory to an suppressive phenotype, or the 34 T cells directly interact with CD1d on a highly suppressive subpopulation of T regulatory cells killing them.
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