Cited by 2,914T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4

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Tivol, Elizabeth A., Borriello, Frank, Schweitzer, A.Nicola, Lynch, William P., Bluestone, Jeffrey A., Sharpe, Arlene H.·1995·Immunity

Abstract

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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Crossref · 10.1016/1074-7613(95)90125-6

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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
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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