Differential therapeutic modulation of exhaustion among autoreactive and global CD8 T cells in type 1 diabetes (T1D)

Abstract

Abstract Islet-specific CD8 T cell exhaustion (TEX) is linked to slower progression of type 1 diabetes (T1D). However, in the therapeutic setting, only global TEX has been studied. Here we address whether TEX among autoreactive cells in clinical trials relates to better outcome. We assessed PBMCs from select T1D subjects who had variable preservation of pancreatic function two years after treatment with teplizumab (anti-CD3, n=7) or alefacept (LFA3-Ig, n=12). We applied a CyTOF panel incorporating pooled pancreatic islet autoantigen peptide-loaded MHC Class I tetramer and 18 phenotyping markers. CD8 T cell subsets were identified by DISCOV-R multidimensional clustering analysis and were applied to samples with >5 autoreactive cells. Better clinical outcome was linked to greater frequencies of global CD8 TEX (subsets expressing PD1, EOMES, TIGIT, and KLRG1): a PD1hi subset 2 months after teplizumab (p=0.049) and a CD57hi subset 2 years following alefacept (p=0.044) treatment. Overall, increases in islet-specific TEX were rarely detected in poor responders (1 of 8 subjects with detectable islet-specific cells) consistent with a lack of change in global TEX, However, in subjects with better preservation of beta cell function, islet-specific TEX increased in fewer subjects (2 of 6) than global CD8 T cells (4 of 8). Together these results indicate that islet-specific CD8 T cells only partially mirror global CD8 responses, and further research is needed to clarify the role of exhaustion and its relation to autoreactive T cells in determining outcome in therapeutic settings. Supported by grants from NIH (R01 AI141952) and Immune Tolerance Network (UM1AI109565).