ESPEYB19 10. Type 1 Diabetes Pathogenesis (3 abstracts)
Nature 2022;602(7895):156-161. https://pubmed.ncbi.nlm.nih.gov/34847567/
Brief Summary: This study used a well-characterized mouse model of type 1 diabetes (T1D), the non-obese diabetic mouse (NOD), to examine the fate of CD8 T cells over the 530 week course of the disease. They found a stem-like autoimmune progenitor population in the pancreatic draining lymph nodes, which can self-renew and generate short-lived autoimmune mediators that migrate to the pancreas, where they differentiate further and destroy β-cells.
This study provides new insights into the steps leading to T1D in a mouse model, by focusing on CD8 T cells that specifically recognize the β-cell islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Two different populations of IGRP-specific CD8 T cells were identified: one in the pancreatic lymph nodes, showing a high expression of the transcription-factor protein TCF1; and the other in the pancreas, which showed a more differentiated phenotype, including low expression of TCF1. Of note, TCF1 promotes self-renewal and is essential for the maintenance of memory CD8 T cells.
The CD8 T cells in the pancreas represent short-lived cells which destroy β-cells, whereas the lymph nodes cells represent stem-like autoimmune progenitors, with self-renewal properties (due to high expression of TCF1), and able to sustain the pool of cells entering the pancreas. These data show that the autoimmune progenitor cells act as a self-sustaining reservoir in the pancreatic lymph node and are the source of the disease-causing autoimmune mediators. Of note, in contrast to CD8 T cells found in the context of chronic infections or cancer, pancreatic autoimmune T cells do not display a transcriptional or phenotypic TOX-driven exhaustion program (which under conditions of chronic antigen exposure leads to T-cell exhaustion), and thus they retain effector function.
These findings suggest that strategies aimed at targeting the stem-like autoimmune progenitor pool, which represents the seeds for T1D, could emerge as new effective immunotherapy interventions.
References: 1. Lin WW, Nish SA, Yen B, Chen YH, Adams WC, Kratchmarov R, et al. CD8+ T Lymphocyte Self-Renewal during Effector Cell Determination. Cell Rep. 2016 Nov 8;17(7):17731782. 2. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion Nature. 2019 Jul;571(7764):211218.