Cited by 1,685T-cell and B-cell ImmunologyImmunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkers

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CTLA-4 is a second receptor for the B cell activation antigen B7.

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Linsley, P S, Brady, W, Urnes, M, Grosmaire, L S, Damle, N K, Ledbetter, J A·1991·The Journal of experimental medicine

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Abstract

Functional interactions between T and B lymphocytes are necessary for optimal activation of an immune response. Recently, the T lymphocyte receptor CD28 was shown to bind the B7 counter-receptor on activated B lymphocytes, and subsequently to costimulate interleukin 2 production and T cell proliferation. CTLA-4 is a predicted membrane receptor from cytotoxic T cells that is homologous to CD28 and whose gene maps to the same chromosomal band as the gene for CD28. It is not known, however, if CD28 and CTLA-4 also share functional properties. To investigate functional properties of CTLA-4, we have produced a soluble genetic fusion between the extracellular domain of CTLA-4 and an immunoglobulin C gamma chain. Here, we show that the fusion protein encoded by this construct, CTLA4Ig, bound specifically to B7-transfected Chinese hamster ovary cells and to lymphoblastoid cells. CTLA4Ig also immunoprecipitated B7 from cell surface 125I-labeled extracts of these cells. The avidity of 125I-labeled B7Ig fusion protein for immobilized CTLA4Ig was estimated (Kd approximately 12 nM). Finally, we show that CTLA4Ig was a potent inhibitor of in vitro immune responses dependent upon cellular interactions between T and B lymphocytes. These findings provide direct evidence that, like its structural homologue CD28, CTLA-4 is able to bind the B7 counter-receptor on activated B cells. Lymphocyte interactions involving the B7 counter-receptor are functionally important for alloantigen responses in vitro.

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Maker, A. V., Phan, G. Q., Attia, P., Yang, J. C., Sherry, R. M., Topalian, S. L., Kammula, U. S., Royal, R. E., Haworth, L. R., Levy, C. L., et al. (2005) · Annals of Surgical Oncology · doi:10.1245/aso.2005.03.536 · Cited by 492
“The complexity of this relationship has been further elucidated by the role of cytotoxic T lymphocyte–associated antigen (CTLA)-4, a close homologue of CD28 that binds to members of the B7 family with a higher affinity than does CD28.(3)”
BackgroundInfluential
Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.
Lin, H., Bolling, S. F., Linsley, P. S., Wei, R. Q., Gordon, D., Thompson, C. B., & Turka, L. A. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.178.5.1801 · Cited by 485
Self-citation
Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers
Han, S., Hathcock, K. S., Zheng, B. Q., Kepler, T. B., Hodes, R. J., & Kelsoe, G. H. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.2.556 · Cited by 480
Renal Transplantation
Suthanthiran, M., & Strom, T. B. (1994) · New England Journal of Medicine · doi:10.1056/nejm199408113310606 · Cited by 479
Following the fate of individual T cells throughout activation and clonal expansion. Signals from T cell receptor and CD28 differentially regulate the induction and duration of a proliferative response.
Wells, A. D., Guðmundsdóttir, H., & Turka, L. A. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119873 · Cited by 460
PD‐1/PD‐L1 pathway: Basic biology and role in cancer immunotherapy
Salmaninejad, A., Valilou, S. F., Shabgah, A. G., Aslani, S., Alimardani, M., Pasdar, A., & Sahebkar, A. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28358 · Cited by 445
“At low antigen concentrations, PD‐ L2/PD‐1 interactions inhibit strong B7‐CD28 signals.”
BackgroundInfluential
T cell responses: naïve to memory and everything in between
Pennock, N. D., White, J. T., Cross, E. W., Cheney, E. E., Tamburini, B. A., & Kedl, R. M. (2013) · Advances in Physiology Education · doi:10.1152/advan.00066.2013 · Cited by 461
Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1.
Tan, P., Anasetti, C., Hansen, J. A., Melrose, J. E., Brunvand, M. W., Bradshaw, J., Ledbetter, J. A., & Linsley, P. S. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.177.1.165 · Cited by 461
Self-citation
The MHC Class I-Like IgG Receptor Controls Perinatal IgG Transport, IgG Homeostasis, and Fate of IgG-Fc-Coupled Drugs
Roopenian, D. C., Christianson, G. J., Sproule, T. J., Brown, A. C., Akilesh, S., Jung, N., Petkova, S. B., Avanessian, L., Choi, E. Y., Shaffer, D. J., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.7.3528 · Cited by 454
“on day 3 with PBS or 20 g purified CTLA-4 Ig (27) and 20 g anti-CD40 ligand (CD40L) IgG1 (28) in PBS (kindly provided by B.”
Method
Immunosuppressive strategies in transplantation
Denton, M., Magee, C., & Sayegh, M. H. (1999) · The Lancet · doi:10.1016/s0140-6736(98)07493-5 · Cited by 445
THE DYNAMICS OF T CELL RECEPTOR SIGNALING: Complex Orchestration and the Key Roles of Tempo and Cooperation
Germain, R. N., & Štefanová, I. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.467 · Cited by 441
Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade.
Hurwitz, A. A., Foster, B. A., Kwon, E. D., Truong, T. N., Choi, E. M., Greenberg, N. M., Burg, M. B., & Allison, J. P. (2000) · PubMed · Cited by 425
Transplantation of Anergic Histoincompatible Bone Marrow Allografts
Guinan, E. C., Boussiotis, V. A., Neuberg, D. S., Brennan, L., Hirano, N., Nadler, L. M., & Gribben, J. G. (1999) · New England Journal of Medicine · doi:10.1056/nejm199906033402202 · Cited by 427
PD-L1:CD80 Cis-Heterodimer Triggers the Co-stimulatory Receptor CD28 While Repressing the Inhibitory PD-1 and CTLA-4 Pathways
Zhao, Y., Lee, C. K., Lin, C.-H., Gassen, R. B., Xu, X., Huang, Z., Xiao, C., Bonorino, C., Lu, L.-F., Bui, J. D., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.11.003 · Cited by 383
“CTLA-4 outcompetes CD28 for their shared ligands, CD80 and CD86, in part because of its higher binding affinity to these ligands (Krummel and Allison, 1995; Linsley et al., 1991; van der Merwe et al., 1997).”
Background
Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection
Hancock, W. W., Sayegh, M. H., Zheng, X.-G., Peach, R., Linsley, P. S., & Turka, L. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.13967 · Cited by 412
Self-citation
T Cell Exhaustion
Baessler, A., & Vignali, D. A. A. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-110914 · Cited by 420
Targeting FAK in anticancer combination therapies
Dawson, J. C., Serrels, A., Stupack, D. G., Schlaepfer, D. D., & Frame, M. C. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00340-6 · Cited by 407
LIGHT, a TNF-Like Molecule, Costimulates T Cell Proliferation and Is Required for Dendritic Cell-Mediated Allogeneic T Cell Response
Tamada, K., Shimozaki, K., Chapoval, A. I., Zhai, Y., Su, J., Chen, S.-F., Hsieh, S.-L. E., Nagata, S., Ni, J., & Chen, L. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.8.4105 · Cited by 395
Organ transplantation—how much of the promise has been realized?
Lechler, R. I., Sykes, M., Thomson, A. W., & Turka, L. A. (2005) · Nature Medicine · doi:10.1038/nm1251 · Cited by 390
“Transiently blocking CD28-B7 costimulation using either monoclonal antibodies or CTLA4I”
Method
Restriction of PD-1 function by cis -PD-L1/CD80 interactions is required for optimal T cell responses
Sugiura, D., Maruhashi, T., Okazaki, I.-M., Shimizu, K., Maeda, T. K., Takemoto, T., & Okazaki, T. (2019) · Science · doi:10.1126/science.aav7062 · Cited by 386
Costimulatory blockade in patients with rheumatoid arthritis: A pilot, dose‐finding, double‐blind, placebo‐controlled clinical trial evaluating CTLA‐4Ig and LEA29Y eighty‐five days after the first infusion
Moreland, L. W., Alten, R., den Bosch, F. E. V., Appelboom, T., Leon, M., Emery, P., Cohen, S. B., Luggen, M. E., Shergy, W. J., Nuamah, I. F., et al. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10294 · Cited by 383
Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis
Martin, R., McFarland, H. F., & Boggs, J. M. (1995) · Critical Reviews in Clinical Laboratory Sciences · doi:10.3109/10408369509084683 · Cited by 376
Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade
Nakamoto, N., Cho, H., Shaked, A., Olthoff, K., Valiga, M. E., Kaminski, M., Gostick, E., Price, D. A., Freeman, G. J., Wherry, E. J., et al. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000313 · Cited by 380
“Induced in activated T cells and constitutively expressed in FoxP3 + Tregs[22,23], CTLA-4 shares its ligands B7-1 and B7-2 with CD28 but binds them with differential kinetics[19,24,25].”
Background
Absence of B7-dependent responses in CD28-deficient mice
Green, J. M., Noel, P. J., Sperling, A. I., Walunas, T. L., Gray, G. S., Bluestone, J. A., & Thompson, C. B. (1994) · Immunity · doi:10.1016/1074-7613(94)90092-2 · Cited by 376
CTLA-4: a negative regulator of autoimmune disease.
Karandikar, N. J., Vanderlugt, C. L., Walunas, T. L., Miller, S. D., & Bluestone, J. A. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.184.2.783 · Cited by 376
The role of CD40 in the regulation of humoral and cell-mediated immunity
Durie, F. H., Foy, T. M., Masters, S. R., Laman, J. D., & Noelle, R. J. (1994) · Immunology Today · doi:10.1016/0167-5699(94)90269-0 · Cited by 373
At the Bench: Preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy
Intlekofer, A. M., & Thompson, C. B. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.1212621 · Cited by 387
“ogy with CD28 and bound to the same B7 ligands [23, 24].”
Background
CD28, CTLA‐4 and their ligands: who does what and to whom?
Sansom, D. M. (2000) · Immunology · doi:10.1046/j.1365-2567.2000.00121.x · Cited by 374
B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation.
Murphy, E. E., Terres, G., Macatonia, S. E., Hsieh, C., Mattson, J. D., Lanier, L. L., Wysocka, M., Trinchieri, G., MURPHY, K. M. M., & O’Garra, A. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.180.1.223 · Cited by 351
Mechanisms of costimulation
Sharpe, A. H. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00784.x · Cited by 359
“The CD28 homolog cytotoxic T lymphocyteassociated antigen-4 (CTLA-4) (8) was found to be a higher affinity binding partner for B7-1 and B7-2, when compared with CD28 (9).”
Background

Authors: Linsley, P. S., Brady, W., Urnes, M., Grosmaire, L. S., Damle, N. K., & Ledbetter, J. A.
Affiliations: Bristol-Myers Squibb (United States) (US)
ORCID: Linsley, P S
Venue: The Journal of experimental medicine
Publisher: Rockefeller University Press
Published: 1991-09-01
Volume: 174
Issue: 3
Pages: 561-569
ISSN: 0022-1007 (ISSN-L)
1540-9538
DOI: 10.1084/jem.174.3.561
PMC: PMC2118936
OpenAlex: W2087013294
Cited by: 1,685
References: 41
Citations by year: 2026: 14 · 2025: 31 · 2024: 49 · 2023: 37 · 2022: 35 · 2021: 49 · 2020: 51 · 2019: 55 · 2018: 49 · 2017: 49 · 2016: 59 · 2015: 52 · 2014: 39 · 2013: 41 · 2012: 39
FWCI: 27.78
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: The Journal of Experimental Medicine (publishedVersion)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Funders: Bristol-Myers Squibb
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords: CTLA-4, B7, CD28, T cell costimulation, B cell activation, T cell-B cell interaction, soluble receptor, interleukin-2, alloantigen response, cytotoxic T lymphocytes
MeSH terms: Abatacept, Amino Acid Sequence, Animals, Antigens, Differentiation, Antigens, Surface, B-Lymphocytes, Base Sequence, Cell Line, Ligands, Lymphocyte Cooperation, Lymphocyte Activation, Molecular Sequence Data, Oligonucleotides, Precipitin Tests, Receptors, Immunologic, Recombinant Fusion Proteins, T-Lymphocytes, Antigens, CD, B7-1 Antigen, Immunoconjugates, CTLA-4 Antigen, In Vitro Techniques

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CTLA-4 is a second receptor for the B cell activation antigen B7.

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