Single-cell transcriptomics of CD8 T cells in autoimmune diabetes after anti-CD3 monoclonal antibody treatment

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Abstract The FcR non-binding anti-CD3 mAb, teplizumab is the first drug approved by FDA to delay Type 1 diabetes (T1D) by modulating the immune mediated destruction of insulin-producing β cells. However, 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. To understand how the antibody induces long-term tolerance, we performed single-cell RNA-seq and TCR-seq on T cells from the islets and pancreas-draining lymph nodes (pLN) of long-term remitted NOD mice treated by anti-CD3 mAb or pre-diabetic NOD mice with insulitis. In the islets, CD8 T cells of remitted NOD had higher expressions of TCF-1 and EOMES, than their counterparts from pre-diabetic control. Notably, CD8 T cells from islets of remitted NOD had increased expressions of TOX and EOMES while with no difference in TCF-1, compared to their counterparts from paired pLN. In contrast, islet-infiltrating CD8 T cells of pre-diabetic NOD had decreased expressions of EOMES and TCF-1 but with no difference in TOX, compared to their pLN counterparts. Moreover, islet-infiltrating CD8 T cells of remitted NOD had higher median TCR entropy indicating a more diverse TCR repertoire than their counterparts from pre-diabetic NOD. These results suggest that anti-CD3 modulates the terminal differentiation of islet-infiltrating CD8 T cells. Tolerance is maintained by cells with stem-like and exhaustion features and a more diverse TCR repertoire.

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