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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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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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“It has been reported that CTLA-4 secreted by Treg is able to disrupt the CD80/ PD-L1 heterodimer on antigen-presenting cells, resulting in an increase of free PD-L1 (66).”
BackgroundInfluentialOzone Pollution, Oxidative Stress, Regulatory T Cells and Antioxidants
Rivas-Arancibia, S., Hernández-Orozco, E., Rodrı́guez-Martı́nez, E., Valdés‐Fuentes, M., Cornejo-Trejo, V., Pérez-Pacheco, N., Dorado-Martı́nez, C., Zequeida-Carmona, D., & Caleti, I. E. (2022) · Antioxidants · doi:10.3390/antiox11081553 · Cited by 45
“The inhibitory role of Treg cells depends on cell contact-dependent inhibition through CD80/CD86 on APC cells, mainly dendritic cells, by the CTLA-4 receptor expressed on Treg cells [81].”
BackgroundLi, K., Li, J., Wei, X., Wang, J., Geng, M., Ai, K., Liang, W., Zhang, J., Li, K., Gao, H., et al. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200335 · Cited by 46
Prevention of Metabolic Syndrome by Phytochemicals and Vitamin D
Santa, K., Kumazawa, Y., & Nagaoka, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032627 · Cited by 44
“Cancer immune therapy requires the activation of cellular immunity [124], and the elimination of parasites that have infected the body requires the activation of humoral immunity [125].”
BackgroundLi, R., Li, H., Yang, X., Hu, H., Liu, P., & Liu, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.970508 · Cited by 42
“As mentioned above, Tregs can release soluble PD-L1 on the surface of DCs when they endocytose CD80/86 in a CTLA-4dependent manner, which boosts the tolerance of DCs (70).”
BackgroundImmunometabolism of regulatory T cells in cancer
Saravia, J., & Chi, H. (2025) · Oncogene · doi:10.1038/s41388-025-03458-1 · Cited by 45
“CTLA4 + T reg cells also directly extract CD80 and CD86 co-stimulatory molecules from APCs via trogocytosis [35], and intratumoral DCs show increased expression of these molecules upon depletion of intratumoral T reg cells [36].”
CD4+ T-cell subsets in autoimmune hepatitis: A review
Chen, H., Han, Z., Fan, Y., Chen, L., Peng, F., Cheng, X., Wang, Y., Su, J., & Li, D. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000269 · Cited by 41
Regulatory T-cells: The Face-off of the Immune Balance
Singer, M., Elsayed, A. M., & Husseiny, M. I. (2024) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2911377 · Cited by 44
Implications of regulatory T cells in anti-cancer immunity: from pathogenesis to therapeutics
Dwivedi, M., Tiwari, S., Kemp, E. H., & Begum, R. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e10450 · Cited by 38
Immune checkpoint inhibitors and reproductive failures
Chen, Z., Huang, J., Kwak-Kim, J. Y.-H., & Wang, W. (2023) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2023.103799 · Cited by 38
Yu, H., Xue, W., Yu, H., Song, Y., Liu, X., Qin, L., Wang, S., Bao, H. F., Gu, H., Chen, G., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.171417 · Cited by 38
“Several studies have demonstrated that ICOS facilitates the production of antiinflammatory factors, whereas CTLA4 helps to maintain the suppressive activity of Tregs (18, 19).”
BackgroundMikami, N., Kawakami, R., Sugimoto, A., Arai, M., & Sakaguchi, S. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adr6049 · Cited by 39
Self-citationKennedy, A., Robinson, M. A., Hinze, C., Waters, E., Williams, C., Halliday, N., Dovedi, S. J., & Sansom, D. M. (2023) · The EMBO Journal · doi:10.15252/embj.2022111556 · Cited by 37
“Using this system, we also investigated the role of the CTLA-4 cytoplasmic domain, since it has been suggested that CTLA-4 can remove CD80 from CD80:PD-L1 co-expressing cells via trogocytosis (Tekguc et al , 2021), a process not requiring its cytoplasmic domain.”
BackgroundResultInfluentialTregs integrate native and CAR-mediated costimulatory signals for control of allograft rejection
Rosado‐Sánchez, I., Haque, M., Salim, K., Speck, M., Fung, V. C. W., Boardman, D. A., Mojibian, M., Raimondi, G., & Levings, M. K. (2023) · JCI Insight · doi:10.1172/jci.insight.167215 · Cited by 37
“As such, we hypothesized that in an immunocompetent in vivo setting, CD28 naturally expressed by the CAR-Tregs may engage CD80/86 on APCs and compensate for a weak or absent CAR-encoded costimulatory signal.”
Wang, Q., Huang, X., Zhou, S., Ding, Y., Wang, H., Jiang, W., & Xu, M. (2022) · International Journal of Genomics · doi:10.1155/2022/2723264 · Cited by 36
Cell-based therapies for rheumatoid arthritis: opportunities and challenges
Li, Y.-J., & Chen, Z. (2022) · Therapeutic Advances in Musculoskeletal Disease · doi:10.1177/1759720x221100294 · Cited by 34
Li, J., Niu, J., Min, W., Ai, J., Xu, L., Miao, J., Zhou, S. Y., Liang, Y., Chen, S., Ren, Q., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01026-8 · Cited by 34
“B7-1 plays an important role in this process [21].”
Zhang, Z., Ji, W., Huang, J., Zhang, Y., Zhou, Y., Zhang, J., Dong, Y., Yuan, T., Yang, Q., Ding, X., et al. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.1072 · Cited by 33
PD-1 and CTLA-4 exert additive control of effector regulatory T cells at homeostasis
Pereira, J. A., Lanzar, Z. R., Clark, J. T., Hart, A. P., Douglas, B. B., Shallberg, L. A., O’Dea, K. M., Christian, D. A., & Hunter, C. A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.997376 · Cited by 37
“In addition, the ability of CTLA-4 to bind with high affinity to CD80 means that it can outcompete the ability of CD28 to provide costimulation and can actively restrict APC function through CTLA-4 mediated trogocytosis of CD80 (34).”
BackgroundResultInfluentialZhang, C., Li, Y., Yu, Y., Li, Z., Xu, X., Talifu, Z., Liu, W., Yang, D., Gao, F., Wei, S., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1334828 · Cited by 32
Dysregulation of T cell response in the pathogenesis of inflammatory bowel disease
Chandwaskar, R., Dalal, R., Gupta, S. K., Sharma, A., Parashar, D., Kashyap, V. K., Sohal, J. S., & Tripathi, S. K. (2024) · Scandinavian Journal of Immunology · doi:10.1111/sji.13412 · Cited by 32
“126 In line with this, the role of CTLA4 in Tregs functions was further demonstrated using Foxp3-specific deletion of CTLA-4.”
Cole, M., Anastasiou, P., Lee, C., Yu, X., de Castro, A., Roelink, J., Moore, C., Mugarza, E., Jones, M. L., Valand, K., et al. (2024) · Science Advances · doi:10.1126/sciadv.adl6464 · Cited by 33
“Second, T regs can compete with CD8 + and CD4 + T cells for the costimulatory molecules on the antigen-presenting cells, primarily by transendocytosis or trogocytosis of CD80/CD86 through the interaction with CTLA-4 ( 50 , 51 ).”
Mechanisms of Resistance to Anti-PD-1 Immunotherapy in Melanoma and Strategies to Overcome It
Zielińska, M. K., Ciążyńska, M. A., Sulejczak, D., Rutkowski, P. L., & Czarnecka, A. M. (2025) · Biomolecules · doi:10.3390/biom15020269 · Cited by 30
“Moreover, the balance of CD80 and CD86 expression on APCs significantly influences Treg-mediated suppression, with each molecule interacting differently with CD28 and CTLA-4 to modulate immune responses [84,85].”
CD40-CD154: A perspective from type 2 immunity
Díaz, Á., González-Alayón, I., Pérez-Torrado, V., & Suárez‐Martins, M. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101528 · Cited by 30
Krempski, J. W., Lama, J. K., Iijima, K., Kobayashi, T., Matsunaga, M., & Kita, H. (2022) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2022.02.024 · Cited by 31
Zhang, S., Chen, W., Zhou, Y., Zheng, X., Fu, Y., Liu, H., Wan, Z., & Zhao, Y. (2023) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.3c12560 · Cited by 29
A coordinated cellular network regulates tolerance to food
Rudnitsky, A., Oh, H., Margolin, M., Dassa, B., Shteinberg, I., Stoler‐Barak, L., Shulman, Z., & Kedmi, R. (2025) · Nature · doi:10.1038/s41586-025-09173-x · Cited by 37
“Together, these results suggest that RORγt APCs, not ILC3s, have a unique role in instructing the dietary pT reg cell program.”
InfluentialDouble Negative T Regulatory Cells: An Emerging Paradigm Shift in Reproductive Immune Tolerance?
Bafor, E. E., Valencia, J. C., & Young, H. A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.886645 · Cited by 29
Regulatory T cells in cancer: from immunosuppression to therapeutic targeting
Basurto-Olvera, P., Serrano, H., & Maldonado‐Bernal, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1703211 · Cited by 34
Clinical and Immunological Effects of p53-Targeting Vaccines
Zhou, S., Fan, C., Zeng, Z., Young, K. H., & Li, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.762796 · Cited by 29
“…exert their immunosuppressive activity through various cellular and humoral mechanisms, including cytotoxic T lymphocyte antigen 4 (CTLA-4)- mediated suppression of APCs, consumption of IL-2, and production of immune inhibitory cytokines and molecules (Spolski et al., 2018; Tekguc et al., 2021).”
BackgroundAire suppresses CTLA-4 expression from the thymic stroma to control autoimmunity
Morimoto, J. O., Matsumoto, M., Miyazawa, R., Yoshida, H., Tsuneyama, K., & Matsumoto, M. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110384 · Cited by 28
Functional Diversities of Regulatory T Cells in the Context of Cancer Immunotherapy
Gao, R., Shi, G., & Wang, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.833667 · Cited by 29
“This process allows CLTA-4 to remove CD80/86 on APC surface via a trogocytosis mechanism, followed by trans-endocytosis for intracellular degradation (40, 42, 43).”
BackgroundInfluentialEras of designer Tregs: Harnessing synthetic biology for immune suppression
Tuomela, K., Salim, K., & Levings, M. K. (2023) · Immunological Reviews · doi:10.1111/imr.13254 · Cited by 30
Augmenting regulatory T cells: new therapeutic strategy for rheumatoid arthritis
Zhang, J., Liu, H.-J., Chen, Y.-H., Liu, H., Zhang, S., Yin, G., & Xie, Q.-B. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1312919 · Cited by 25
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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