Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3
Open accessAbstract
Impaired chronic viral and tumor clearance has been attributed to CD8+ T cell exhaustion, a differentiation state in which T cells have reduced and altered effector function that can be partially reversed upon blockade of inhibitory receptors. The role of the exhaustion program and transcriptional networks that control CD8+ T cell function and fate in autoimmunity is not clear. Here we show that intra-islet CD8+ T cells phenotypically, transcriptionally, epigenetically and metabolically possess features of canonically exhausted T cells, yet maintain important differences. This 'restrained' phenotype can be perturbed and disease accelerated by CD8+ T cell-restricted deletion of the inhibitory receptor lymphocyte activating gene 3 (LAG3). Mechanistically, LAG3-deficient CD8+ T cells have enhanced effector-like functions, trafficking to the islets, and have a diminished exhausted phenotype, highlighting a physiological role for an exhaustion program in limiting autoimmunity and implicating LAG3 as a target for autoimmune therapy.
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Exhausted autoantigen-specific CD8+ T cells were detected in murine and human type 1 diabetes.
“T cell exhaustion may play a role in AIDs, 33-35 and exhausted autoantigen-specific CD8 + T cells were detected in murine and human type 1 diabetes (T1D). 35,36”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [36]
The Results (‘Autoreactive CD8+ T cells express hallmarks of exhaustion’; page unavailable) identify β-cell-antigen-reactive CD8+ T cells in NOD mice, and the Discussion describes a subset as exhaustion-like rather than canonically exhausted. The cited paper’s reported findings do not establish their detection in humans with type 1 diabetes, so the human portion of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExhausted CD8 and CD4 T cells are present in inflamed tissues of T1D and SLE models.
“and exhausted CD8 and CD4 T cells are present in inflamed tissues of T1D 36,62 and systemic lupus erythematosus (SLE) 63 models.”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [36]
The Results (‘Autoreactive CD8+ T cells express hallmarks of exhaustion’; page unavailable) identify an exhaustion-like subset of CD8+ T cells in the islets of NOD mice, a T1D model. The paper does not establish that intra-islet CD4+ T cells are exhausted. The SLE portion of the citing sentence is attached to a different citation (63), not this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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- Authors
- Grebinoski, S., Zhang, Q., Cillo, A. R., Manne, S., Xiao, H., Brunazzi, E. A., Tabib, T., Cardello, C., Lian, C. G., Murphy, G. F., Lafyatis, R., Wherry, E. J., Das, J., Workman, C. J., & Vignali, D. A. A.
- Affiliations
- University of Pittsburgh (US)
- Boston Children's Hospital (US)
- University of Pennsylvania (US)
- Brigham and Women's Hospital (US)
- Parker Institute for Cancer Immunotherapy (US)
- Corresponding author
- Vignali, Dario A. A.
- ORCID
- Venue
- Nature Immunology
- Published
- 2022-05-26
- Volume
- 23
- Issue
- 6
- Pages
- 868-877
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC9179227
- OpenAlex
- W4281565387
- Cited by
- 107
- References
- 84
- Citations by year
- 2026: 20 · 2025: 21 · 2024: 38 · 2023: 25 · 2022: 3
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK089125)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (AI144422, AI108545, AI147638, AI089443, AI105343, AI117950, AI082630, AI112521, AI115712)
- U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (CA210944)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- CD8+ T cell exhaustion, LAG-3, type 1 diabetes, autoimmunity, pancreatic islets, T cell metabolism, T cell migration, inhibitory receptors, nonobese diabetic mouse, T cell fate
- MeSH terms
- Humans, Neoplasms, Phenotype, Autoimmunity, CD8-Positive T-Lymphocytes
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