Cytoskeletal regulation of self-reactive T cell restimulation and effector functions in the pancreatic islets


Center University of Colorado Denver
Award Year 2021
Pilot Study Cytoskeletal regulation of self-reactive T cell restimulation and effector functions in the pancreatic islets
Awardee Jordan Jacobelli PhD ORCiD
Abstract

Islet-specific T cell entry in the islets and antigenic restimulation at the disease site are key steps leading to islet destruction in type 1 diabetes (T1D). The T cell cytoskeleton plays a crucial role in regulating T cell migration and interaction with Antigen Presenting Cells (APC) and target cells. However, there is a key knowledge gap about the mechanism by which specific cytoskeletal effectors regulate T cell functions at the autoimmune disease site. Formin-like-1 (FMNL1) is a cytoskeletal effector highly expressed in T cells. Our data show that FMNL1 knock-out (KO) T cells are significantly impaired in inducing T1D in a mouse T cell transfer model. Furthermore, our preliminary data show that FMNL1-deficient T cells have impaired motility within lymph nodes and reduced T cell-APC interactions. Based on these data, we hypothesize that FMNL1-deficient islet-reactive T cells are less pathogenic due to reduced migration, activation and effector functions within the pancreatic islets. We will employ a multi-pronged approach, including genetic, immunological, and in vivo imaging techniques, to determine the role of FMNL1 in auto-reactive T cell pathology in T1D. Our work will also validate FMNL1 as a potential target to inhibit T cell mediated pathogenesis as a treatment for T1D.