Cited by 491T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

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Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells

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Tekguc, Murat, Wing, James Badger, Osaki, Motonao, Long, Jia, Sakaguchi, Shimon·2021·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.2023739118PMC PMC8325248

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Abstract

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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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
ORCID: Tekguc, Murat
Wing, James Badger
Osaki, Motonao
Long, Jia
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
DOI: 10.1073/pnas.2023739118
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
Licence: www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 184 d)
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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Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells

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