High-dimensional mass imaging of muscle for the mechanistic study of T cells in inclusion body myositis

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PROJECT SUMMARY/ABSTRACT Sporadic inclusion body myositis (IBM) is a rare, acquired muscle disease of unknown etiology. Our long-term goal is to define how T cells contribute to the pathogenesis of IBM. T cells undergo clonal expansion and differentiation but lose their proliferative capacity and exhibit characteristics of senescence, including production of cytolytic proteins (e.g. perforin and granzyme) that promote muscle cell death. Further, senescent T cells are resistance to apoptosis, which may explain the treatment refractory nature of IBM. The objective of the current study is to define molecular attributes of senescence in highly-differentiated T cells, and correlate these features with clinical measures of IBM. Further, a pharmacological approach will be used to define the mechanism regulating T cell senescence in IBM. We will test the central hypothesis that senescent muscle T cells promote the severity and progression of IBM. In preliminary studies, we show that the frequency of KRLG1+CD8+ senescent-like T cells was elevated in the blood of IBM patients. Although KRLG1+CD8+ T cells correlated with disease duration, they did not correlate with the severity of IBM. Given that an immune response can vastly differ between blood and the affected tissue, mechanistic studies with high-resolution profiling of the immune response in IBM muscle are needed to determine relationships between senescent T cells and IBM. The central hypothesis of this investigation will be tested by addressing two specific aims. In specific aim 1, we will define the molecular features of senescent muscle T cells and their relationship to disease severity and progression. The lack of tools to rigorously phenotype T cell populations in muscle has made it difficult to study these cells and determine their function in IBM. Thus, an innovative high-dimensional mass imaging platform will be used to address this limitation, and determine the relationship between senescent T cells and IBM. In specific aim 2, we will determine the ability of senolytic therapy to ablate senescent CD8+ T cells, which will provide mechanistic insight on the regulation of T cell senescence during IBM. The proposed study is significant as it will establish a foundation for defining the function of dysregulated T cell responses in IBM. Further, it will provide preliminary evidence to support the testing of a novel therapeutic approach for this disease. The proposed research is also innovative as it uses cutting-edge advancements in mass imaging to rigorously interrogate the senescent phenotype of T cells in IBM. The use of senolytic drugs also marks an innovative approach for targeting dysfunctional T cells and defining the role of senescent T cells in IBM. Collectively, the proposed work promises to advance our understanding of the role of the immune system in the pathogenesis of IBM, and may have a broad impact by guiding the development of novel strategies to treat and/or cure IBM.