Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance

Abstract

Type 1 diabetes (T1D) affects over a million Americans, and disease incidence is on the rise. Despite decades of research, there is still no cure for this disease. Exciting beta cell replacement strategies are being developed, but in order for such approaches to work, targeted immunotherapies must be designed. To selectively halt the autoimmune response, researchers must first understand how this response is regulated and which tolerance checkpoints fail during T1D development. Herein, we discuss the current understanding of T1D pathogenesis in humans, genetic and environmental risk factors, presumed roles of CD4+ and CD8+ T cells as well as B cells, and implicated autoantigens. We also highlight studies in non‐obese diabetic mice that have demonstrated the requirement for CD4+ and CD8+ T cells and B cells in driving T1D pathology. We present an overview of central and peripheral tolerance mechanisms and comment on existing controversies in the field regarding central tolerance. Finally, we discuss T cell– and B cell–intrinsic tolerance mechanisms, with an emphasis on the roles of inhibitory receptors in maintaining islet tolerance in humans and in diabetes‐prone mice, and strategies employed to date to harness inhibitory receptor signaling to prevent or reverse T1D.

BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design

“…Besides protection against TB, BCG has other clinical applications, especially in two main immunotherapy fields: treatments for cancer and autoimmune diseases, such as melanoma and type-1 diabetes (T1D), respectively (we summarize the contribution of BCG to immunotherapy in Figure 2). T1D is an autoimmune disease characterized by the destruction of pancreatic beta cells (72). This destruction leads to a lack of insulin production, which leads to the development of hyperglycemia, polyuria, and hypoinsulinemia (73).…”

From Pancreatic β-Cell Gene Networks to Novel Therapies for Type 1 Diabetes

“…On the other hand, cytokines such as IFNa and IFNg induce the expression of potentially protective molecules in human islets, namely, PDL1 and HLA-E (7,10), a finding confirmed by histology of insulin-containing islets from patients affected by T1D (9,10). PDL1 is a ligand of PD1, a protein expressed in T cells, and PDL1-PD1 binding inhibits T cell function: for instance, overexpression of PDL1 in b-cells protects mice against immune-mediated diabetes, while inhibiting PD1-PDL1 in the context of immune checkpoint therapy for metastatic tumors triggers immune-mediated endocrine diseases, including T1D (22). HLA-E is a potential inhibitor of both natural killer and T cells (7).…”

From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations

“…The current understanding is that islet cells are both the driver for and the target of the autoimmune T1DM. It is widely believed that genetic predisposition underlies individual susceptibility to the disease ( 34 ). However, monozygotic twins do not exhibit identical susceptibility to T1DM, which indicates the contribution of additional factors, such as metabolic stress ( 35 ), viral infection ( 34 ) and changes in the intestinal microbiota ( 36 ).…”

“…It is widely believed that genetic predisposition underlies individual susceptibility to the disease ( 34 ). However, monozygotic twins do not exhibit identical susceptibility to T1DM, which indicates the contribution of additional factors, such as metabolic stress ( 35 ), viral infection ( 34 ) and changes in the intestinal microbiota ( 36 ). As a result of impaired thymic education, islet-specific autoreactive lymphocytes migrate from the pancreas-draining lymph nodes to the islets, where they mediate β-cell destruction ( 35 , 37 ).…”