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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Background
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“2) (Linsley et al, 1991, 1994).”
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Background
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Background
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BackgroundInfluential
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Background
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“Some of these signals are generated when CD28 on the T cell binds to B7 on the antigen-presenting cell.”
BackgroundInfluential
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“Schneider et al. [84] demonstrated that CTLA-4 increases T cell motility and prevents the formation of stable contacts between T cells and APC, providing a potential mechanism by which CTLA-4 may modulate the activation of T cells.”
Background
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“Activated T-cells expressing CTLA4 impede the interaction between B7-1 and B7-2 molecules on APCs and CD28, and thereby induce anergy and reduce T-cell activation[108-110].”
Ex Vivo Alloanergization with Belatacept: A Strategy to Selectively Modulate Alloresponses after Transplantation
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“2 are ligands for the T-cell counterreceptor CD28 and also the inhibitory counter-receptor CTLA4 (15).”
Influential
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Vétizou, M., Daillère, R., & Zitvogel, L. (2016) · médecine/sciences · doi:10.1051/medsci/20163211013 · Cited by 21
Isolation of Two Novel Human Anti-CTLA-4 mAbs with Intriguing Biological Properties on Tumor and NK Cells
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“It has been proposed that the negative signal delivered by CTLA-4 on T cells, where it is mainly present as an intracellular protein, but transiently exposed on the surface of activated T cells [7], is due to its high affinity binding for B7-1/B7-2 ligands [8] on antigen-presenting cells [9,10], thus interfering in th…”
Background
Biologic and advanced immunomodulating therapeutic options for sarcoidosis: a clinical update
Obi, O. N., Lower, E. E., & Baughman, R. P. (2021) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2021.1878024 · Cited by 20
“It binds more avidly to CD80 than CD86 on antigen-presenting cells and results in reduced T-cell activation [405,415].”
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B7-H3: another molecule marker for Mo-DCs?
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CTLA-4: From conflict to clinic
Bashyam, H. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.2046fta · Cited by 20
Abatacept Does Not Induce Direct Gene Expression Changes in Antigen-Presenting Cells
Carman, J., Davis, P. M., Yang, W.-P., Zhu, J., Han, C. L., He, A., Truong, A. B., Suchard, S. J., & Nadler, S. G. (2009) · Journal of Clinical Immunology · doi:10.1007/s10875-009-9282-z · Cited by 20
Abatacept and its use in the treatment of rheumatoid arthritis (RA) in the Czech Republic—data from the ATTRA registry
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“Abatacept is a soluble fusion protein combining the Fc portion of IgG1 and CTLA4 which prevents the binding of CD28 to CD80/CD86 molecule [2].”
Background
Signaling Amplification at the Immunological Synapse
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Prolongation of Cardiac Graft Survival with Anti-CD4Ig Plus hCTLA4Ig in Primates
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Soluble costimulatory factors sCD28, sCD80, sCD86 and sCD152 in relation to other markers of immune activation in patients with myasthenia gravis
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Targeting and Blocking B7 Costimulatory Molecules on Antigen-Presenting Cells Using CTLA4Ig-Conjugated Liposomes: In Vitro Characterization and in Vivo Factors Affecting Biodistribution
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“The affinity of CTLA-4 for B7 molecules is 20-fold higher than that of CD28 for B7 (2,3).”
Background
Macaque CD4 + T-Cell Subsets: Influence of Activation on Infection by Simian Immunodeficiency Viruses (SIV)
FIRPO, P. P., Axberg, I., Scheibel, M., & Clark, E. A. (1992) · AIDS Research and Human Retroviruses · doi:10.1089/aid.1992.8.357 · Cited by 20
Modulation of T cell proliferative responses by accessory cell interactions
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B7+-transfectant tubular epithelial cells induce T cell anergy, ignorance or proliferation
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Co‐stimulation by anti‐immunoglobulin is required for B cell activation by CD40Llow T cells
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Novel Molecular Subtypes Associated With 5mC Methylation and Their Role in Hepatocellular Carcinoma Immunotherapy
Mo, Z., Cao, Z., Luo, S., Chen, Y., & Zhang, S. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.562441 · Cited by 19
A systematic review and meta-analysis of immune checkpoint therapy in relapsed or refractory non-Hodgkin lymphoma; a friend or foe?
Davoodi‐Moghaddam, Z., Jafari‐Raddani, F., Noori, M., & Bashash, D. (2023) · Translational Oncology · doi:10.1016/j.tranon.2023.101636 · Cited by 21
“However, it has an opposite function, and its affinity for binding to the ligands is significantly higher [8,9].”
Background
CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner
Lo, J. W., Schroeder, J.-H., Beattie, G., Roberts, L. B., Cozzetto, D., Omer, O., Ross, E. M., Heuts, F. W. H., Jowett, G. M., Read, E., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51719-6 · Cited by 21
CTLA‐4Ig blocks the development and progression of citrullinated fibrinogen–induced arthritis in DR4‐transgenic mice
Yue, D., Brintnell, W. C., Mannik, L. A., Christie, D. A., Haeryfar, S. M. M., Madrenas, J., Chakrabarti, S., Bell, D., & Cairns, E. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27597 · Cited by 19
Immunomodulatory effects induced by cytotoxic T lymphocyte antigen 4 immunoglobulin with donor peripheral blood mononuclear cell infusion in canine major histocompatibility complex–haplo-identical non-myeloablative hematopoietic cell transplantation
Chen, Y., Fukuda, T., Thakar, M. S., Kornblit, B. T., Storer, B. E., Santos, E. B., Storb, R. F., & Sandmaier, B. M. (2011) · Cytotherapy · doi:10.3109/14653249.2011.586997 · Cited by 19
Effects of Different Up-Dosing Regimens for Hymenoptera Venom Immunotherapy on Serum CTLA-4 and IL-10
Riccio, A., Saverino, D., Pesce, G., Rogkakou, A., Severino, M. G., Bonadonna, P., Ridolo, E., Mauro, M., Canonica, G. W., Bagnasco, M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037980 · Cited by 19
“An effective T-cell activation requiresaprimary signaldeliveredby theantigenicpeptidepresented by major histocompatibility complex molecules and a non-specific signal (co-stimulation) mediated by the interaction of CD28 with B7 familymembers (CD80,CD86)expressedonantigen-presentingcells [3].”
BackgroundInfluential
Influence of CD80 and CD86 Co-Stimulation in the Modulation of the Activation of Antigen Presenting Cells
Mir, M. A., & Agrewala, J. N. (2007) · Current Immunology Reviews · doi:10.2174/157339507781483487 · Cited by 19
“CD152 functions to provide a "negative" signal to the T cell that inhibits cytokines production and arrests cell cycle progression thus limiting immune responses [17-19].”
Background
Neurological complications of immune checkpoint inhibitor cancer immunotherapy
Zivelonghi, C., & Ζεκερίδου, Α. (2021) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2021.117424 · Cited by 22
IL-10+CTLA-4+ Th2 Inhibitory Cells Form in a Foxp3-Independent, IL-2–Dependent Manner from Th2 Effectors during Chronic Inflammation
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Monocyte activation by apoptotic cells removal in systemic lupus erythematosus patients
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Short peptides sensitize target cells to CTL specific for the MHC class Ib molecule, H2-M3
Dabhi, V. M., & Fischer Lindahl, K. (1998) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199811)28:11

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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