Cited by 109T-cell and B-cell ImmunologyDiabetes and associated disordersCancer Immunotherapy and Biomarkers

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Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3

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Grebinoski, Stephanie, Zhang, Qianxia, Cillo, Anthony R., Manne, Sasikanth, Xiao, Hanxi, Brunazzi, Erin A., Tabib, Tracy, Cardello, Carly, Lian, Christine G., Murphy, George F., Lafyatis, Robert, Wherry, E. John, Das, Jishnu, Workman, Creg J., Vignali, Dario A. A.·2022·Nature Immunology

DOI 10.1038/s41590-022-01210-5PMC PMC9179227

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Abstract

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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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: Grebinoski, Stephanie
Zhang, Qianxia
Cillo, Anthony R.
Manne, Sasikanth
Xiao, Hanxi
Tabib, Tracy
Cardello, Carly
Lian, Christine G.
Murphy, George F.
Lafyatis, Robert
Wherry, E. John
Das, Jishnu
Workman, Creg J.
Vignali, Dario A. A.
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2022-05-26
Volume: 23
Issue: 6
Pages: 868-877
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/s41590-022-01210-5
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3

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