T Cell Differentiation in Autoimmune Type 1 Diabetes

Type 1 diabetes (T1D) is a progressive T cell-mediated autoimmune disease that results from the breakdown of tolerance mechanisms in β-cell-specific T cells. Although CD8 T cells are primarily responsible for the destruction of insulin-producing β cells, intriguingly, HLA class II allelic polymorphisms confer the greatest genetic risk for the development of T1D, suggesting a critical role of CD4 T cells in disease initiation and progression. Many aspects of autoimmune T cell differentiation remain enigmatic, including where and how autoimmune CD8 and CD4 T cells arise, which molecular programs control autoimmune T cell differentiation, and how CD8 T cells sustain β-cell destruction in the face of persistent self-antigen encounter. In this work, we summarize our current understanding of β-cell-specific CD8 and CD4 T cell differentiation and function, the role of autoimmune stem-like progenitor CD8 T cells in initiating and sustaining disease, and molecular programs and key transcription factors associated with the diabetogenic T cell response.