Decoding the role of CD4 T cells in driving autoimmune type 1 diabetes 2333351

Abstract Introduction Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease where CD8 T cells eliminate insulin-producing β cells in the pancreatic islets. Yet, MHC class II haplotypes confer the greatest genetic risk for the development of T1D, suggesting a critical role for CD4 T cells. Employing the non-obese diabetic (NOD) mouse model, our lab identified in the pancreatic lymph node (pLN) a stem-like β cell-specific CD8 T cell pool required to initiate and sustain disease: pLN β cell-specific stem-CD8 T cells self-renew and continuously give rise to differentiated progenies which migrate to the pancreas (PA) and eliminate β cells; the pLN stem-CD8 T cell pool is absolutely required to sustain β cell destruction. Given the importance of autoimmune stem-CD8 T cells and the association of MHC class II in T1D pathogenesis, we wanted to understand the role of CD4 T cells in autoimmune CD8 T cell stemness and differentiation. Methods We employed the NOD model and longitudinally assessed the phenotypic and functional characteristics of β cell-specific CD4 T cells using flow cytometry, serial transplantation, CRISPR/Cas9-mediated gene editing, and transcriptomic studies. Results Our studies reveal, for the first time, how CD4 T cells drive autoimmune CD8 T cell stemness, differentiation, and pathogenicity. We find β cell-specific CD4 T cells in pLN and PA reveal two distinct populations based on their expression of TCF1, a transcription factor critical for stemness and self-renewal. Functional studies identify pLN TCF1hi CD4 T cells as stem-T cell subset needed to drive the generation and maintenance of autoimmune stem-CD8 T cells in pLN, their differentiation into β cell-destroying cytotoxic effector cells, and ultimately T1D. Conclusion A unique population of β cell-specific CD4 T cells in pLN is critical for autoimmune CD8 T cell stemness, differentiation and disease. Identifying therapeutic strategies that target autoimmune stem-CD4 T cells could emerge as powerful approaches for the treatment of T1D. Funding Source NIH grant 1F31DK145180, NIH grant R01AI173249, Juvenile Diabetes Research Foundation grant JDRF SRA-2023-1410-S-B, Topic Categories Basic Autoimmunity (BA)