Anti-CD3 mAb treatment reshapes infiltrating T and β cells in the islets in autoimmune diabetes
Ying Wu, Maxwell Spurrell, Ana Lledó-Delgado, Songyan Deng, Dejiang Wang, Yang Liu, Mahsa Nouri Barkestani, Ana Luisa Perdigoto, Kevan C. Herold
Ying Wu, Maxwell Spurrell, Ana Lledó-Delgado, Songyan Deng, Dejiang Wang, Yang Liu, Mahsa Nouri Barkestani, Ana Luisa Perdigoto, Kevan C. Herold
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Research Article Endocrinology Immunology

Anti-CD3 mAb treatment reshapes infiltrating T and β cells in the islets in autoimmune diabetes

Abstract

Treatment with anti-CD3 monoclonal antibody (mAb) can delay or prevent type 1 diabetes in mice and humans by modulating the immune-mediated destruction of β cells. A single course of treatment may have lasting efficacy, but the mechanisms that account for these prolonged effects, i.e., “operational tolerance,” are not clear. Here, we used paired single-cell RNA and T cell receptor sequencing to characterize islet-infiltrating T cells and their counterpart in paired pancreatic lymph nodes from anti-CD3 mAb–treated nonobese diabetic (NOD) mice in remission. We found that after anti-CD3 mAb treatment, T cells that infiltrate the islets are more heterogeneous and have hybrid features including characteristics of T stem cell–like memory and reduced effector function compared with those from untreated prediabetic NOD mice. Autoantigen-reactive CD8+ T cells persist after treatment, but they also show features of stemness and reduced pathogenicity. Our findings describe the reshaping of islet-infiltrating and autoreactive T cells and β cells that lead to operational, but tenuous, tolerance to autoimmune diabetes following anti-CD3 mAb treatment.

Authors

Ying Wu, Maxwell Spurrell, Ana Lledó-Delgado, Songyan Deng, Dejiang Wang, Yang Liu, Mahsa Nouri Barkestani, Ana Luisa Perdigoto, Kevan C. Herold

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Figure 1

Peripheral blood and islet-infiltrating cells in remitter NOD mice after anti-CD3 mAb treatment.

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Peripheral blood and islet-infiltrating cells in remitter NOD mice after...
(A) Newly diabetic NOD mice (n = 24) were treated with the F(ab′)2 fragments of anti-CD3 mAb 145-2C11 (5 μg/d for 3 or 4 days, i.p.) and were considered in remission with blood glucose lower than 250 mg/dL for ≥9 weeks after the treatment (remission: n = 14; non-response: n = 8; relapse: n = 2). Glucose levels after anti-CD3 mAb treatment are shown. (B) CD8+ T cells from blood of NOD mice with remission after anti-CD3 treatment were examined for expression of PD-1, KLRG1, and TIGIT by flow cytometry (dashed line = 250 mg/dL for blood glucose level) (*P = 0.0133 for PD-1 expression and *P = 0.0294 for TIGIT expression at day 7 vs. day 0, ANOVA for repeated measures with Dunnett’s multiple-comparison test). (C) Representative H&E images show insulitis in islets from an untreated prediabetic NOD mouse (insulitis score = 2), a remitter NOD mouse after anti-CD3 treatment (insulitis score = 2), a prediabetic NOD mouse 3 days after anti-CD3 treatment (insulitis score = 1), and an untreated diabetic NOD mouse (insulitis score = 3) (green arrows point at infiltrates). Original magnification, ×10. (D) Bar chart showing insulitis scores of untreated prediabetic (Pre DM; DM, diabetes mellitus) NOD mice (14 islets from 3 mice), prediabetic NOD mice 3 days after anti-CD3 treatment (46 islets from 3 mice), anti-CD3–treated remitter NOD mice (17 islets from 4 mice), and untreated diabetic (Untx DM) NOD mice (19 islets from 5 mice). A significant difference was found comparing all the 4 conditions (χ2 test, P < 0.0001). Insulitis was significantly lower 3 days after treatment in anti-CD3–treated prediabetic versus untreated prediabetic NOD mice (χ2 test, *P = 0.018). (E) Immunohistochemical images showing islets from a remitter NOD mouse stained by anti-CD3 (in brown) and anti-CD19, respectively. Original magnification, ×10.