Using single cell RNA sequencing to unravel the regulation and maintenance of effector function in exhausted T cells in autoimmune diabetes
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2025
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Melbourne Authors
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Medicine (St Vincent's)
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PhD thesis
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Open Access
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© 2025 David John De George
Abstract
Type 1 diabetes is a chronic autoimmune disorder involving the specific destruction of insulin-producing pancreatic beta cells, predominantly by autoreactive cytotoxic CD8+ T cells. The only current treatment for T1D is the burdensome administration of exogenous insulin which, though lifesaving for many, still falls short of the extra-ordinary, real-time control of glucose metabolism provided by the endogenous beta cell. Thus, immunotherapies targeting the immune-mediated destruction of these cells in the first place are urgently needed. The recent success of teplizumab highlights the potential efficacy of targeting T cells in T1D, however, despite clear roles for T cells in beta cell destruction, we know relatively little about the phenotype and regulation of autoreactive CD8+ T cells, which is required for the development of targeted immunotherapies.
In this study, I used single cell RNA sequencing to study immune cell heterogeneity in the non-obese diabetic (NOD) mouse model of autoimmune diabetes, with a particular focus on CD8+ T cells. I found that most islet-infiltrating antigen-experienced CD8+ T cells had entered the exhaustion program and used an integrated, paired gene expression and TCR atlas of PD-1+IGRP-specific T cells from islets, pancreatic lymph node and other peripheral lymphoid organs to uncovered previously unknown heterogeneity and relationships among exhausted T cells in NOD mice. Despite their exhausted phenotype, these cells remained functional, and many maintained progenitor or stem-like states (TPEX), even in islets. This usually lymph node-restricted and rare state sustains long-term CD8+ T cell responses in other settings of chronic antigen exposure and is the functional mediator of immune checkpoint therapy responses. Finally, using NOD-TII mice, with exhaustion-inducing, widespread IGRP expression, and Ifngr1-mutant NOD mice, with abrogated IFN-gamma signalling, I have uncovered putative regulators of sustained TPEX cells and cytotoxicity in exhausted autoreactive T cells, including common gamma chain cytokine and mTOR signalling. These findings lay the foundations for novel and specific immunotherapies targeting T cell exhaustion to prevent primary beta cell destruction in T1D.
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Type 1 diabetes, Non-obese diabetic mouse, T cell, Exhaustion, IGRP, Cytokines, Autoimmunity, Beta cell, Pancreatic islet