Molecular and cellular insights into T cell exhaustion

Wherry, E. John; Kurachi, Makoto

doi:10.1038/nri3862

Cited by 4,652T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersImmune Cell Function and Interaction

Molecular and cellular insights into T cell exhaustion

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Wherry, E. John, Kurachi, Makoto·2015·Nature Reviews Immunology

DOI 10.1038/nri3862PMC PMC4889009

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Abstract

In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called 'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.

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T cell exhaustion is characterized by progressive loss of cytokine expression, proliferative potential, and upregulation of inhibitory receptors.
“Other situations of chronic antigen stimulation, such as cancer or chronic viral infections, result in T cell exhaustion, characterized by the progressive loss of cytokine expression, proliferative potential, and upregulation of inhibitory receptors (immune checkpoints).”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [32]
Exhaustion can be partially reversed by immune checkpoint inhibitors.
“Exhaustion can be partially reversed by immune checkpoint inhibitors, providing the basis for successful therapies against cancer. 32,33”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [32]
In the tumor microenvironment, prolonged antigen exposure leads to T cell exhaustion, marked by losing effector functions.
“In TME, prolonged antigen exposure leads to T cell exhaustion, marked by losing effector functions.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [24]
The exhausted subset overexpressed Lag3, Tbc1d4, Sostdc1, and Tnfsf8.
“cells with an exhaustion signature (denoted exhausted, fig. S3B) overexpressing the Lag3, Tbc1d4, Sostdc1, and Tnfsf8 genes (22, 31)”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [31]

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“Tex cells are defined by poor effector functions, high co-expression of multiple inhibitor receptors and an altered global transcriptional program compared to functional Teff or Tmem cells (Wherry and Kurachi, 2015).”
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Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade
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The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction
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A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer
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Peripheral T cell expansion predicts tumour infiltration and clinical response
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T cells expressing an anti–B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma
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Brain immunology and immunotherapy in brain tumours
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T cell subsets and functions in atherosclerosis
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Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma
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Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?
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CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer
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Biology and regulation of IL-2: from molecular mechanisms to human therapy
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The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness
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Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19
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Metabolic barriers to cancer immunotherapy
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Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics
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Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion
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Multidimensional communication in the microenvirons of glioblastoma
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Authors: Wherry, E. J., & Kurachi, M.
Affiliations: University of Pennsylvania (US)
Corresponding author: Wherry, E. John
Kurachi, Makoto
ORCID: Wherry, E. John
Kurachi, Makoto
Venue: Nature Reviews Immunology
Publisher: Springer Science and Business Media LLC
Published: 2015-07-24
Volume: 15
Issue: 8
Pages: 486-499
ISSN: 1474-1733 (ISSN-L)
1474-1741
DOI: 10.1038/nri3862
PMC: PMC4889009
OpenAlex: W1910012553
Cited by: 4,652
References: 156
Citations by year: 2026: 563 · 2025: 494 · 2024: 518 · 2023: 508 · 2022: 517 · 2021: 551 · 2020: 441 · 2019: 381 · 2018: 306 · 2017: 227 · 2016: 129 · 2015: 12 · 2014: 1
FWCI: 21.14
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Public Health Service (HHSN266200500030C)
National Institute of Allergy and Infectious Diseases (HHSN266200500030C, AI 082630, R01AI105343, AI095608, AI105343, AI112521, P01AI112521, U01AI095608, U19AI082630)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Keywords: T cell exhaustion, chronic viral infection, cancer immunotherapy, inhibitory receptors, persistent antigen, inflammatory signals, transcriptional programs, therapeutic target
MeSH terms: Bacterial Infections, Gene Expression Regulation, Humans, Immunologic Memory, Lymphocyte Activation, Neoplasms, T-Lymphocytes, Cytotoxic, Transcription, Genetic, Virus Diseases, Signal Transduction, Cytokines, Clonal Anergy, CD57 Antigens, T-Lymphocytes, Regulatory

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Molecular and cellular insights into T cell exhaustion

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