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.
Bibliographical noteFunding Information:
The National Institutes of Health R01 AI106791, P01 AI35296, U24 AI118635, Leona M. and Harry B. Helmsley Charitable Trust 2018PG-T1D058, Minnesota Partnership for Biotechnology and Medical Genomics MNP#18.01, Regenerative Medicine of Minnesota #11215 TR002 (B.T.F.), the Frieda Martha Kunze Fellowship (T.M.), and anonymous donations through the University of Minnesota Foundation fund 11724 “Diabetes Cure Research Using Immune Regulation and Tolerance” supported this work. We thank the members of the Fife laboratory Dr. Justin Spanier, Dr. Jason Mitchell, Chris Tucker, Linnea Swanson, Alexander Dwyer, Jenna Johnson, and Lovejot Singh for helpful discussions, and Drs. Kristin Hogquist, Vaiva Vezys, Bryce Binstadt, and Christopher Pennell for their feedback.
© 2019 New York Academy of Sciences.
- cytotoxic T lymphocyte-associated protein-4
- lymphocyte activation gene-3
- non-obese diabetic mice
- programmed death-1
- type 1 diabetes