Despite expression of exhaustion markers, CD8 Treg are a cytolytic population that targets pathogenic CD4s to prevent beta cell destruction by Type 1 Diabetes peripheral blood mononuclear cells 4194

Abstract Description CD8 regulatory T cells (CD8 Treg) play a crucial role in maintaining immune system balance by their cytolytic elimination of pathogenic immune cells. CD8 Treg appear exhausted in patients with autoimmune diseases, based on expression of canonical markers including PD1, TIM3, LAG3 and KLRG1. This study sought to investigate the activity and phenotype of CD8 Treg isolated from patients with Type 1 Diabetes (T1D). Stimulation of T1D peripheral blood mononuclear cells (PBMC) with a self-peptide cocktail illustrated that CD8 Treg from T1D patients were unable to control pathogenic T cell responses. CD8 Treg from T1D patients showed reduced intracellular Granzyme B compared to healthy donors. Activation resulted in enhancement of granzyme B and killing of target cells, suggesting CD8 Treg are a population that natively expresses high levels of exhaustion markers, as opposed to a functionally exhausted population. In pancreatic organoid co-cultures, T1D PBMCs produced proinflammatory cytokines, and reduced viable beta cells and glucose-stimulated insulin secretion. Addition of CD8 Treg to pancreatic organoids suggested that CD8 Treg can prevent tissue destruction in an islet model by killing of pathogenic CD4 cells. Our data highlights the therapeutic potential for restoration of CD8 Treg functions in T1D patients to delay or prevent T cell mediated beta islet cell destruction. Topic Categories Therapeutic Approaches to Autoimmunity (THER)