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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. +7 more·2011·Science

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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  • 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.”
  • 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).”
  • 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].”

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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.
Venue
Science
Published
2011-04-29
Volume
332
Issue
6029
Pages
600-603
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
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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