Teplizumab induces persistent changes in the antigen-specific repertoire in individuals at risk for type 1 diabetes
Ana Lledó-Delgado, … , John S. Tsang, Kevan C. Herold
Ana Lledó-Delgado, … , John S. Tsang, Kevan C. Herold
Published August 13, 2024
Citation Information: J Clin Invest. 2024;134(18):e177492. https://doi.org/10.1172/JCI177492.
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Teplizumab induces persistent changes in the antigen-specific repertoire in individuals at risk for type 1 diabetes

Abstract

BACKGROUND Teplizumab, a non-FcR-binding anti-CD3 mAb, is approved to delay progression of type 1 diabetes (T1D) in at-risk patients. Previous investigations described the immediate effects of the 14-day treatment, but longer-term effects of the drug remain unknown.METHODS With an extended analysis of study participants, we found that 36% were undiagnosed or remained free of clinical diabetes after 5 years, suggesting operational tolerance. Using single-cell RNA sequencing, we compared the phenotypes, transcriptome, and repertoire of peripheral blood CD8+ T cells including autoreactive T cells from study participants before and after teplizumab and features of responders and non-responders.RESULTS At 3 months, there were transcriptional signatures of cell activation in CD4+ and CD8+ T cells including signaling that was reversed at 18 months. At that time, there was reduced expression of genes in T cell receptor and activation pathways in clinical responders. In CD8+ T cells, we found increased expression of genes associated with exhaustion and immune regulation with teplizumab treatment. These transcriptional features were further confirmed in an independent cohort. Pseudotime analysis showed differentiation of CD8+ exhausted and memory cells with teplizumab treatment. IL7R expression was reduced, and patients with lower expression of CD127 had longer diabetes-free intervals. In addition, the frequency of autoantigen-reactive CD8+ T cells, which expanded in the placebo group over 18 months, did not increase in the teplizumab group.CONCLUSION These findings indicate that teplizumab promotes operational tolerance in T1D, involving activation followed by exhaustion and regulation, and prevents expansion of autoreactive T cells.TRIAL REGISTRATION ClinicalTrials.gov NCT01030861.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases/NIH, Juvenile Diabetes Research Foundation.

Authors

Ana Lledó-Delgado, Paula Preston-Hurlburt, Sophia Currie, Pamela Clark, Peter S. Linsley, S. Alice Long, Can Liu, Galina Koroleva, Andrew J. Martins, John S. Tsang, Kevan C. Herold

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Figure 6

CD127 expression levels predict response to teplizumab.

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CD127 expression levels predict response to teplizumab. (A–C) Flow cytom...
(A–C) Flow cytometry data of TN10 trial showing the difference in the MFI of CD127+ EMRA CD8+ T cells (TEMRA CD8+ T cells) (A), MFI CD127+ CM CD8+ T cells (B), and percentages of CD127+ CM CD8+ T cells (C) between teplizumab and placebo at different time points (*P < 0.05, **P < 0.01, n = 38 teplizumab, 28 placebo). The means + SEM from the mixed model are shown. (D) Kaplan Meier curves showing the difference between the median time to onset of T1D in teplizumab-treated patients with values above or below the median of the MFI of CD127 on TEMRA CD8+ cells in the placebo-treated patients at 3 months. The median times to stage 3 T1D were 83.2 months in the teplizumab-treated patients with MFI CD127 on CD8+ TEMRA cells below the median (n = 25) and 24.5 months for those above the median (n = 8) (log-rank P = 0.046). (E) The same comparison based on the median MFI of CD127 on CD8+ TEMRA cells in teplizumab-treated patients at 18 months. The median times to stage 3 T1D are 83.2 months with MFI below the median (n = 26) and 42.6 months with values below the median (n = 6) (log-rank P = 0.017). (F) Cox regression model showing the association between the time to diagnosis with stage 3 T1D based on a quantitative measure of the MFI of CD127 on TEMRA CD8+ cells in the teplizumab-treated group at 3 months (n = 32) (P = 0.05).