NPJ autoimmunityPub Date : 2026-01-01Epub Date: 2026-10-01DOI: 10.1038/s44483-026-00002-5
Robert C Sharp, Matthew E Brown, Leeana D Peters, Rhonda Bacher, Laura M Jacobsen, Todd M Brusko
{"title":"Type 1 diabetes <i>SIRPG</i> risk variants increase SIRP<i>γ</i> expression and CD47 loss enhances CD8<sup>+</sup> T cell cytotoxicity.","authors":"Robert C Sharp, Matthew E Brown, Leeana D Peters, Rhonda Bacher, Laura M Jacobsen, Todd M Brusko","doi":"10.1038/s44483-026-00002-5","DOIUrl":"https://doi.org/10.1038/s44483-026-00002-5","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) risk variants within <i>SIRPG</i> 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<sup>+</sup> and CD8<sup>+</sup> 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<sup>+</sup> T cells, as well as a pancreatic β-cell line (βLox5). <i>CD47</i>-deficient T cells displayed heightened activation, reduced co-inhibitory receptor expression, and increased production of IL-2 and TNF following stimulation. Furthermore, <i>CD47</i> KO CD8<sup>+</sup> T cell avatars expressing an HLA-A*02:01-restricted, IGRP<sub>265-273</sub>-reactive T cell receptor (TCR) exhibited enhanced cytotoxicity toward βLox5 targets, while <i>CD47</i> 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.</p>","PeriodicalId":524223,"journal":{"name":"NPJ autoimmunity","volume":"1 1","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149123886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NPJ autoimmunityPub Date : 2026-01-01Epub Date: 2026-09-10DOI: 10.1038/s44483-026-00001-6
Taruna Lamba, George C Tsokos
{"title":"Neurotransmitters as regulators of autoimmunity: mechanisms and translational targeting.","authors":"Taruna Lamba, George C Tsokos","doi":"10.1038/s44483-026-00001-6","DOIUrl":"10.1038/s44483-026-00001-6","url":null,"abstract":"<p><p>Autoimmune diseases arise from sustained breakdown of immune tolerance, chronic activation of innate and adaptive immune responses, and progressive tissue damage. Although cytokines, antigen receptor signaling, and genetic susceptibility have traditionally been considered the principal drivers, increasing evidence demonstrates that neurotransmitters have an underappreciated role in the pathogenesis of autoimmune diseases. The neuroimmune interactions link neural activity, psychological stress, and tissue innervation to autoimmune disease development, progression, and relapse. In this review, we integrate current mechanistic studies demonstrating how neurotransmitters regulate innate and adaptive immune responses and discuss their role in autoimmune diseases.</p>","PeriodicalId":524223,"journal":{"name":"NPJ autoimmunity","volume":"1 1","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149043427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}