Abstract
Type 1 diabetes (T1D) is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial cells (EC) lining capillary walls into the islets of Langerhans, interaction of T cells with macrophages in the islets, and killing of β-cells by autoreactive CD8+ T cells. Overall, pathogenic cell-cell interactions are likely regulated by the individual’s collection of genetic T1D-risk variants. To accurately model the role of genetics, it is essential to build systems to interrogate single candidate genes in isolation during the interactions of cells that are essential for disease development. However, obtaining single-donor matched cells relevant to T1D is a challenge. Sourcing these genetic variants from human induced pluripotent stem cells (iPSC) avoids this limitation. Herein, we have differentiated iPSC from one donor into DC, macrophages, EC, and β-cells. Additionally, we also engineered T cell avatars from the same donor to provide an in vitro platform to study genetic influences on these critical cellular interactions. This proof of concept demonstrates the ability to derive an isogenic system from a single donor to study these relevant cell-cell interactions. Our system constitutes an interdisciplinary approach with a controlled environment that provides a proof-of-concept for future studies to determine the role of disease alleles (e.g. IFIH1, PTPN22, SH2B3, TYK2) in regulating cell-cell interactions and cell-specific contributions to the pathogenesis of T1D.
Highlights
Type 1 diabetes (T1D) is a debilitating autoimmune disease that is caused by T cell-mediated destruction of b-cells in the islets of Langerhans in the pancreas
While T1D develops in genetically at-risk individuals, our current understanding of the pathogenesis of T1D in humans continues to evolve due to the complexities of genetic risk in combination with environmental factors [52]
Due to the impact of total combined genetic risk, it is necessary to sufficiently power mechanistic studies with large sample sizes to determine the responsibility of a single polymorphism to T1D and the cell types influenced by the greater than 100 polymorphisms that are linked to T1D [1,2,3,4,5,6,7,8,9,10,11,12]
Summary
Type 1 diabetes (T1D) is a debilitating autoimmune disease that is caused by T cell-mediated destruction of b-cells in the islets of Langerhans in the pancreas. This results in lifelong dependence on exogenous insulin and can lead to many complications that degrade quality of life for patients living with T1D. Numerous implicated genes cluster into pathways likely to create situations where different combinations of candidate genes can contribute to increased T1D risk [16]. The utility of iPSC to investigate the relationship between rare and common gene variants and gene expression in pluripotent cells was recently highlighted [17]
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