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Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells
Open accessAbstract
Significance Immunosuppressive Tregs constitutively express CTLA-4, an immune checkpoint receptor. Addressing the role of CTLA-4 in Treg-suppressive function, we show that Treg-expressed CTLA-4, even in the absence of its cytoplasmic portion, promoted the conjugation of Tregs and antigen-presenting cells (APCs), leading to CTLA-4–dependent trogocytosis of CD80/CD86 and concomitant transfer of membrane fragments from APCs to the Treg cell surface. The depletion or blockade of CD80 by trogocytosis or solubilized CTLA-4, respectively, increased free PD-L1 by disrupting cis-CD80/PD-L1 heterodimers on APCs. Thus, Tregs can exert dual suppressive effects through the limitation of CD80/CD86 and up-regulation of free PD-L1 on APCs. Cancer immunotherapy with anti–CTLA-4 and anti–PD-1/PD-L1 blocking antibodies may enhance tumor immunity by hindering this Treg-mediated immune suppression.
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“T cells expressing CTLA4 on the surface can decrease CD80 and CD86 expressions on APCs by undergoing trans‐endocytosis and inhibiting CD28 signaling [297].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [297]
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Metadata
- Authors
- Tekguc, M., Wing, J. B., Osaki, M., Long, J., & Sakaguchi, S.
- Affiliations
- Laboratory of Experimental Immunology, World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University, Suita 565-0871, Japan;
- Immunology Frontier Research Center, The University of Osaka (JP)
- Kyoto University (JP)
- Corresponding author
- Sakaguchi, Shimon
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2021-07-23
- Volume
- 118
- Issue
- 30
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC8325248
- OpenAlex
- W3185714107
- Cited by
- 490
- References
- 53
- Citations by year
- 2026: 116 · 2025: 123 · 2024: 114 · 2023: 72 · 2022: 61 · 2021: 4
- FWCI
- 23.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OUKA (Osaka University Knowledge Archive) (Osaka University) (submittedVersion)
- Funders
- MEXT | Japan Society for the Promotion of Science (16H06295, 18K07175)
- MEXT | JST | Core Research for Evolutional Science and Technology (JP 19gm0010005)
- 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
- regulatory T cells, CTLA-4, trogocytosis, CD80, CD86, PD-L1, antigen-presenting cells, immune checkpoint, cancer immunotherapy
- MeSH terms
- Trogocytosis, Animals, Antigen-Presenting Cells, Dendritic Cells, Female, Lymphocyte Activation, Mice, Inbred BALB C, Mice, Inbred C57BL, B7-1 Antigen, Mice, Knockout, T-Lymphocytes, Regulatory, Mice, B7-2 Antigen, B7-H1 Antigen, CTLA-4 Antigen
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