Autoimmune Type 1 Diabetes (T1D) is characterized by the progressive loss of immune tolerance, leading to the aberrant activation of autoreactive immune cells and the destruction of the insulin-producing β-cells in the pancreas. The main cellular mediators of immune tolerance are Foxp3+ regulatory T cells (Tregs), which play a crucial part in the prevention of autoimmunity. Apart from their classical tasks in taming autoimmune activation, Tregs exert key non-canonical functions in tissues, including the pancreas, to safeguard local homeostasis. We and others have shown that T1D and its pre-symptomatic phase (islet autoimmunity) are characterized by multiple layers of Treg impairments, including impairments in Treg induction, plasticity and stability. Despite these insights into the role of Tregs in regulating islet autoimmunity, little is known about β-cell-related metabolic cues including insulin receptor signaling that can regulate pancreas-residing Tregs.
Functional role of T cell-specific inceptor expression in autoimmunity
Recently, the insulin inhibitory receptor (inceptor) was identified as a negative regulator of insulin signaling on pancreatic β-cells and first analyses using mRNA expression profiles from the Immgen database indicate inceptor expression on T cells. However, the functional role of inceptor on T cells as well as its contribution to aberrant immune activation in autoimmunity remains to be
determined. We have generated T cell and Treg-specific inceptor knockout (KO) mice to dissect the role of inceptor in directing Tregs vs. Th17 cells in the pancreas. First preliminary analyses point towards phenotypic alterations in pancreas-residing T cells in the absence of inceptor with an enhanced proportion of T cells harboring an effector memory phenotype in the KO mice. We will
perform cellular and molecular analyses of CD45+ immune cells in the pancreas of inceptor KO vs. control mice. Using single-cell RNA Sequencing as well as multi-color flow cytometry we will define T cell activation and effector profiles; assess Treg subphenotypes and pancreas-specific Treg clusters together with Treg stability/plasticity. We will decipher extrinsic vs. intrinsic contributions of
inceptor signaling in guiding β-cell – T cell crosstalk. Therefore, analysis of pancreas-specific T cell/Treg differentiation and function will be performed on CD45+ immune cells both from β-cell specific inceptor KO mice as well as from T cell and Treg-specific inceptor KO mice under steady state or proinflammatory conditions. To further link inceptor expression on T cells with autoimmunity, we will induce pancreas autoimmunity in T cell or Treg-specific inceptor KO animals by multiple low-dose injections of streptozotocin, thereby modeling T1D.
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