Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4
Open accessAbstract
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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CTLA-4 removes CD80 and CD86 from antigen-presenting cell surfaces via trans-endocytosis, reducing availability to CD28-expressing T cells.
“CTLA-4 may also remove CD80 and CD86 (including their cytoplasmic domains) from the cell surfaces of antigen-presenting cells via trans-endocytosis (24), therefore reducing the availability of these stimulatory receptors to other CD28-expressing T cells.”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [24]
CTLA-4 blockade most likely impacts T cell activation in draining lymph nodes by CTLA-4-expressing Tregs removing CD80/CD86 from antigen-presenting cells, reducing their ability to stimulate tumor-specific T cells.
“It is thought that the blockade of CTLA-4 most likely impacts the stage of T cell activation in the draining lymph nodes when CTLA-4 expressing Tregs remove CD80/CD86 from the surface of antigen-presenting cells, thereby reducing their ability to effectively stimulate tumor-specific T cells (24).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [24]
CTLA-4 could capture, remove, and degrade its ligands CD80/CD86 from nearby APCs by trans-endocytosis, further hampering the co-stimulatory signal.
“Additionally, CTLA-4 could capture, remove, and degrade its ligands CD80/CD86 from nearby APCs by trans-endocytosis, further hampering the co-stimulatory signal [125].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [125]
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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
- Venue
- Science
- Published
- 2011-04-29
- Volume
- 332
- Issue
- 6029
- Pages
- 600-603
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- 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
- 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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