The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
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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CTLA-4 Control over Foxp3 + Regulatory T Cell Function
Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., & Sakaguchi, S. (2008) · Science · doi:10.1126/science.1160062 · Cited by 2,956
Self-citationTakahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T. W., & Sakaguchi, S. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.2.303 · Cited by 2,233
Self-citationRead, S., Malmström, V., & Powrie, F. M. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.2.295 · Cited by 2,206
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Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4
Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J., Jeffery, L. E., Kaur, S., Briggs, Z., et al. (2011) · Science · doi:10.1126/science.1202947 · Cited by 1,860
Mechanisms of Foxp3+ T Regulatory Cell-Mediated Suppression
Shevach, E. M. (2009) · Immunity · doi:10.1016/j.immuni.2009.04.010 · Cited by 1,787
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Self-citationRegulatory T Cells and Human Disease
Sakaguchi, S., Mikami, N., Wing, J. B., Tanaka, A., Ichiyama, K., & Ohkura, N. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041717 · Cited by 1,163
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Sun, L., Su, Y., Jiao, A., Wang, X., & Zhang, B. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01471-y · Cited by 1,153
Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends
Sun, Q., Hong, Z., Zhang, C., Wang, L., Han, Z., & Ma, D. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01522-4 · Cited by 598
“6 12 Due to the multiple roles of CTLA-4 in initiating and mounting T cell responses, there are many internal regulatory mechanisms in the internal environment.”
BackgroundTumor-infiltrating regulatory T cells as targets of cancer immunotherapy
Tay, C., Tanaka, A., & Sakaguchi, S. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.014 · Cited by 614
Self-citationImmunosuppressive cells in cancer: mechanisms and potential therapeutic targets
Tie, Y., Tang, F., Wei, Y.-Q., & Wei, X.-W. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01282-8 · Cited by 591
Tumor microenvironment signaling and therapeutics in cancer progression
Goenka, A., Khan, F., Verma, B., Sinha, P., Dmello, C. C., Jogalekar, M. P., Gangadaran, P., & Ahn, B. (2023) · Cancer Communications · doi:10.1002/cac2.12416 · Cited by 323
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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