Three-dimensional conformation changes associated with T cell memory and autoimmunity

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ABSTRACT Autoimmune diseases are complex diseases arising from both genetic and environmental factors. The pathogenesis of autoimmune diseases like type 1 diabetes (T1D) is not mediated by a single cell type of the immune system. The role of noncoding variants in these diseases are largely understudied, but suggest that changes in three-dimensional chromatin architecture could be altered. Early work largely focused on the role of CD4+T helper 1 (Th1) and T helper 17 (Th17) cells, followed by T regulatory cells (Tregs). More recently, T memory stem cells (Tscm) were identified and their role in autoimmunity is just beginning to be investigated. These cells possess stem-like properties of self-renewal and differentiation. Unlike memory cells (Tmem), these cells are long-lived, providing a source of prolonged immune memory. Because of their stem cell state and ability to provide long-term memory, these cells have important implications for autoimmunity, cancer immunity and immune therapies, and reconstitution of the immune system. In the context of autoimmunity that means these cells also provide a reservoir of autoreactive and inflammatory cells that can continue disrupt immune function and contribute to chronic disease. Our own data indicate that these cells are enriched in T1D donors compared to healthy control subjects, which may be associated with disease risk alleles. The overall goal of this proposal is to identify two- and three-dimensional chromatin architecture changes that distinguish CD4+ Tscm cells from their naïve progenitor and derived cell fates and determine how changes specific T1D contribute to disease pathogenesis by profiling pure populations of cell from healthy control and T1D subjects. We will determine if T1D-associated change are prevalent in other autoimmune diseases by also profiling Tscms from RA donors. We will determine what role noncoding disease-associated variants at cis-regulatory elements (CREs) might play in this process. We proposed to integrate 2D and 3D chromatin architecture across a large cohort to precisely determine target genes and mechanisms of cell- and disease-specific gene regulation. Specifically, we will identify cell-type specific chromatin architecture in pure populations of CD4+ subtypes related to stem cell memory by employing capture HiC to map regulatory loops across three key cell types in a cohort of 50 healthy control subjects. To determine if these regulatory loops are altered in a diseased state, we will identify T1D-specific chromatin architecture to determine the role of Tscm cells in prolonged inflammation and autoreactivity. Lastly, we will identify chromatin architecture changes common in autoimmune Tscm cells by profiling an addition 50 subjects with rheumatoid arthritis. The proposed study will use innovative approaches to conduct large-scale assessment of 2D and 3D genome architecture to determine cell- and disease-specific gene regulatory mechanisms using a well-defined human cohort. The proposed study will advance our understanding of the role of memory stem cells in autoimmunity and the effects of noncoding variants on chromatin architecture in a disease-specific manner.