Diabetes and other autoimmune endocrine diseases
Type 1 diabetes is an autoimmune disease in which autoreactive cytotoxic CD8 T cells are found in the pancreatic islets, and are actively implicated in the destruction of insulin-secreting β cells. Our group recently tracked multiple, circulating, β cell–reactive CD8 T cells longitudinally in patients with new-onset type 1 diabetes and showed that changes in effector memory (EM) CD8 T cells expressing CD57 were positively correlated with (ie mirrored) changes in β cell function. This suggested that analysis of circulating β cell-reactive CD8 EMs provides a window into understanding ongoing islet immunopathology.
To better understand the molecular basis for these observations, in the present study, we further characterised the transcriptomic profile, chromatin accessibility, and performed single cell TCR and RNA sequencing on CD8 EMs divided according to CD57 expression. Gene signatures of cytolytic/effector function, and expression of transcription factors and receptors known to regulate CD8 differentiation are significantly enhanced in CD57+ EM cells compared with CD57-, suggesting a distinct programme for acquisition of the effector from the memory phenotype. In addition, we simultaneously tracked clonotypes and gene expression at the single cell, epitope-specific level, extending our previous understanding of clonality of CD57+/- EM cells. Multiple identical TCRA/B clones reside in these closely-related but differentially programmed populations.
In summary, we report that CD57 expression is an important distinguishing feature of a subgroup of β cell–specific EM CD8 T cells, with enhanced effector function, that could have therapeutic and biomarker potential in the context of type 1 diabetes.