Anti-CD3 mAb treatment reshapes CD8+ T cells in the islets in autoimmune diabetes 4144

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Abstract Description The humanized FcR non-binding anti-CD3 mAb, teplizumab, delays or prevents type 1 diabetes (T1D) by modulating the immune mediated destruction of beta cells. However, the mechanisms that account for the prolonged clinical effects are not clear. We and others have observed that after remission is induced in diabetic NOD mice that are treated with F(ab’)2 fragments of mAb 145-2C11, insulitis remains. In this study, we characterized single-cell transcriptome and repertoire of whole islets from remitter NOD mice after anti-CD3 treatment, with an aim to better understand the mechanism of the mAb induced long tolerance. Our single-cell analysis revealed that CD8+ T cells in the islets of the remitted NOD mice possess a more diverse repertoire, showing a more naïve-like differentiation trajectory, compared to their counterparts from prediabetic control. Notably, autoreactive CD8+ T cells specific to diabetes antigen IGRP have increased expression of both Tcf7 and Tox in the islets of remitter NOD. Moreover, anti-CD3 treatment also induces remodeling of islet beta cells in remitter NOD mice, directed towards a less dedifferentiated transcriptome. In sum, our findings described alterations in the islets of NOD mice with long remission after anti-CD3 treatment. Islet-infiltrating CD8+ T cells have a more diverse repertoire with a less differentiated transcriptome, whereas islet beta cells are reshaped to a more differentiated state. Topic Categories Basic Autoimmunity (BA)

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