Th17 immunity in human leukocyte antigen DQ8-restricted islet-reactive T-cells is associated with pathogenesis of type 1 diabetes

Background: Autoimmune diabetes (T1D) is a chronic disease that causes severe loss of insulin-producing β cells in the islet. CD4 T cells have a central role in the destruction of β cells, yet the limited knowledge on the phenotype of circulating islet-reactive CD4 T cells restricts our understanding of T1D and impedes the development of more effective diagnostic approaches.

Methods: A modified tetramer-based assay that improves the sensitivity of direct ex vivo detection was developed to study the rare autoreactive CD4 T cells in the periphery. An integrated immunological and bioinformatics approach was used to characterize islet-reactive CD4 T cells specific for HLA-DQ8-restricted immuno-dominant epitopes. 

Results: A highly heterogeneous population was observed within islet-reactive CD4 T cells. Despite the heterogeneity, increased percentages and frequencies of islet-reactive CD4 T cells expressing the Th17 lineage marker CCR6 were found in at-risk (AAb+) and T1D subjects, compared to healthy controls. Correlated with the skewed CCR6 expression, only islet-reactive CD4 T cells from subjects with T1D but not from healthy controls produced IL-17 and IL-21. Notably, cells from one T1D patient predominantly produced IL-4. Single-cell transcriptome analysis of longitudinal at-risk samples revealed extensive TCR clonotype sharing in islet-reactive CD4 T cells, with no public TCR specificity among subjects. Unique genetic signatures, namely the Th17 and Th2 pathways, were also identified from single-cell transcriptomics. 

Conclusion: Our observations suggest that distinct phenotypes are present during progression of T1D, and immune intervention targeting the Th17 pathway could be a promising treatment for some individuals at-risk of or with T1D. In addition, the HLA-DQ8-restricted islet-reactive CD4 T cells investigated in this study could be potential prognostic and predictive biomarkers for the disease.