Type 1 diabetes SIRPG risk variants increase SIRPγ expression and CD47 loss enhances CD8+ T cell cytotoxicity

Abstract

Type 1 diabetes (T1D) risk variants within SIRPG influence transcript splicing and alter the expression of signal regulatory protein gamma (SIRPγ) on human T cells; however, the functional consequences of the risk variants remain poorly defined. Here, we demonstrate that peripheral blood mononuclear cells from individuals carrying a T1D-associated risk haplotype exhibit increased membrane-bound SIRPγ and reduced expression of its ligand CD47 across CD4+ and CD8+ T cell subsets compared to a protective haplotype. To interrogate the impact of impaired CD47 signaling, we generated CRISPR/Cas9 knockout (KO) models in Jurkat and primary human CD8+ T cells, as well as a pancreatic β-cell line (βLox5). CD47-deficient T cells displayed heightened activation, reduced co-inhibitory receptor expression, and increased production of IL-2 and TNF following stimulation. Furthermore, CD47 KO CD8+ T cell avatars expressing an HLA-A*02:01-restricted, IGRP265-273-reactive T cell receptor (TCR) exhibited enhanced cytotoxicity toward βLox5 targets, while CD47 KO βLox5 cells were more susceptible to apoptosis. These findings reveal that CD47 signaling constrains T cell effector function and β-cell susceptibility, and its disruption through altered SIRPγ-ligation may contribute to autoimmune pathogenesis in T1D.