Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4
Open accessAbstract
The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two B7 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation. To elucidate the in vivo function of CTLA-4, we generated CTLA-4-deficient mice. These mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in down-regulating T cell activation and maintaining immunologic homeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.
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CTLA-4 knockout mice develop overwhelming autoimmune lymphoproliferative disease.
“CTLA-4 knockouts (Tivol et al., 1995; Waterhouse et al., 1995), which succumb to overwhelming autoimmune lymphoproliferative disease”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Tivol et al., 1995
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- Authors
- Tivol, E. A., Borriello, F., Schweitzer, A. N., Lynch, W. P., Bluestone, J. A., & Sharpe, A. H.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Chicago (US)
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 1995-11
- Volume
- 3
- Issue
- 5
- Pages
- 541-547
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2076067786
- Cited by
- 2,914
- References
- 29
- Citations by year
- 2026: 42 · 2025: 53 · 2024: 97 · 2023: 123 · 2022: 99 · 2021: 128 · 2020: 141 · 2019: 149 · 2018: 136 · 2017: 133 · 2016: 126 · 2015: 108 · 2014: 96 · 2013: 101 · 2012: 81
- FWCI
- 25.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01ai035225-04)
- National Heart, Lung, and Blood Institute (T32HL007627, T32HLO7627)
- National Institute of Allergy and Infectious Diseases (P01 AI35225)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR042689, 1P30AR42689)
- 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 › Immunotherapy and Immune Responses
- Keywords
- CTLA-4, lymphoproliferation, T cell activation, negative regulation of T cell activation, myocarditis, pancreatitis, lymphocyte infiltration, autoimmunity
- MeSH terms
- Abatacept, Animals, Antigens, Differentiation, Base Sequence, Cells, Cultured, Immunohistochemistry, Lymphocyte Activation, Lymphoid Tissue, Lymphoproliferative Disorders, Mice, Mutant Strains, Mice, Transgenic, Molecular Sequence Data, T-Lymphocytes, Viscera, Down-Regulation, Antigens, CD, Cytokines, DNA Primers, Immunoconjugates, Mice, CTLA-4 Antigen
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