Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes

• 成果类型: Article
• 署名作者: Selck, Claudia; Jhala, Gaurang; De George, David J.; Kwong, Chun-Ting J.; Christensen, Marie K.; Pappas, Evan G.; Liu, Xin; Ge, Tingting; Trivedi, Prerak; Kallies, Axel; Thomas, Helen E.; Kay, Thomas W. H.; Krishnamurthy, Balasubramanian
• 署名单位: St. Vincent's Institute of Medical Research; University of Melbourne; NSW Health; St Vincents Hospital Sydney; St Vincent's Health; St Vincent's Hospital Melbourne; University of Melbourne; Peter Doherty Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10730
• DOI: 10.1073/pnas.2315419121
• 发表日期: 2024-02-06
• 关键词: differentiation; stimulation; destruction; progression; tolerance; infection

摘要

Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (TPEX) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen- driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet- specific glucose - 6- phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs (PLO). More IGRP- specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen- presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP- specific T cells with reduced ability to produce interferon (IFN)gamma, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.