Teplizumab induces persistent changes in the antigen-specific repertoire in individuals at risk for type 1 diabetes
Open accessAbstract
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.
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In people who respond to teplizumab therapy, increases in the frequency of exhausted CD8+ T cells (PD1+ KLRG1+ CD57-) and anergic CD8+ and CD4+ T cells are observed.
“In people who respond to teplizumab therapy, increases in the frequency of exhausted CD8 + T cells (PD1 + KLRG1 + CD57 -) and anergic CD8 + and CD4 + T cells are observed.16,17”
From The future of type 1 diabetes therapy (2025) · cites this paper as [16]
The Discussion (page unavailable) associates CD8+ T-cell exhaustion-related changes with robust responses to teplizumab. The Results describe exhaustion-related signaling and gene expression, but do not report an increased frequency of CD8+ cells with the specified PD1+ KLRG1+ CD57− phenotype or of anergic CD8+ and CD4+ cells in responders (searched: CD57, anergy, and the specified phenotype). (LLM, conf=0.86)
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References 35 · Cited by 58
- Authors
- Lledó-Delgado, A., Preston-Hurlburt, P., Currie, S., Clark, P., Linsley, P. S., Long, S. A., Liu, C., Koroleva, G., Martins, A. J., Tsang, J. S., & Herold, K. C.
- Affiliations
- Yale University (US)
- Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
- Benaroya Research Institute (US)
- National Institutes of Health (US)
- Corresponding author
- Herold, Kevan C.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2024-08-13
- Volume
- 134
- Issue
- 18
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC11405034
- OpenAlex
- W4401541681
- Cited by
- 58
- References
- 35
- Citations by year
- 2026: 28 · 2025: 27 · 2024: 3
- FWCI
- 15.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R01DK057846,R21 AI166387,R01DK129523,P30DK045735,P30S10OD030363. U01 DK061010,U01 DK061034,U01 DK061042,U01 DK061058,U01 DK085453,U01 DK085461,U01 DK085465,U01 DK085466,U01 DK085476,U01 DK085499,U01 DK085504,U01 DK085509,U01 DK103180,U01 DK103153,U01 DK10)
- Juvenile Diabetes Research Foundation International (2-SRA-2019-833-S-B)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- teplizumab, type 1 diabetes, anti-CD3 monoclonal antibody, autoreactive T cells, CD8+ T cell exhaustion, T cell receptor repertoire, operational tolerance, CD127, T cell activation, pseudotime, memory T cell differentiation
- MeSH terms
- Adolescent, Adult, Diabetes Mellitus, Type 1, Female, Humans, Male, CD8-Positive T-Lymphocytes, Antibodies, Monoclonal, Humanized
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