Cited by 1,860T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

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Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell-Extrinsic Function of CTLA-4

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Qureshi, Omar S., Zheng, Yong, Nakamura, Kyoko, Attridge, Kesley, Manzotti, Claire, Schmidt, Emily M., Baker, Jennifer, Jeffery, Louisa E., Kaur, Satdip, Briggs, Zoe, Hou, Tie Z., Futter, Clare E., Anderson, Graham, Walker, Lucy S.K., Sansom, David M.·2011·Science

DOI 10.1126/science.1202947PMC PMC3198051

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Abstract

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.

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Authors: Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J., Jeffery, L. E., Kaur, S., Briggs, Z., Hou, T. Z., Futter, C. E., Anderson, G., Walker, L. S. K., & Sansom, D. M.
Affiliations: University of Birmingham (GB)
University College London (GB)
Corresponding author: Sansom, David M.
ORCID: Qureshi, Omar S.
Zheng, Yong
Nakamura, Kyoko
Attridge, Kesley
Kaur, Satdip
Futter, Clare E.
Anderson, Graham
Walker, Lucy S.K.
Sansom, David M.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2011-04-29
Volume: 332
Issue: 6029
Pages: 600-603
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1202947
PMC: PMC3198051
OpenAlex: W2087482409
Cited by: 1,860
References: 33
Citations by year: 2026: 128 · 2025: 140 · 2024: 153 · 2023: 155 · 2022: 160 · 2021: 151 · 2020: 149 · 2019: 119 · 2018: 126 · 2017: 103 · 2016: 105 · 2015: 100 · 2014: 84 · 2013: 82 · 2012: 68
FWCI: 38.16
Type: journal article
Language: en
Open access: green
publications.aston.ac.uk
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Aston Publications Explorer (Aston University) (acceptedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
UCL Discovery (University College London) (submittedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Funders: Wellcome Trust
Versus Arthritis (17851)
Biotechnology and Biological Sciences Research Council (BB/H013598/1, BB/D011000/1)
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, CD80, CD86, CD28, trans-endocytosis, costimulation, T cell regulation, T cell receptor engagement, antigen-presenting cells, ligand degradation
MeSH terms: Animals, Cricetulus, Dendritic Cells, Endocytosis, Cricetinae, Humans, Ligands, Lymphocyte Activation, Mice, Transgenic, Models, Biological, Ovalbumin, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, Antigens, CD, T-Lymphocyte Subsets, CHO Cells, CD28 Antigens, B7-1 Antigen, Jurkat Cells, T-Lymphocytes, Regulatory, Mice, B7-2 Antigen, CTLA-4 Antigen

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Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell-Extrinsic Function of CTLA-4

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