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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“Superhumanized” Antibodies: Reduction of Immunogenic Potential by Complementarity-Determining Region Grafting with Human Germline Sequences: Application to an Anti-CD28
Tan, P., Mitchell, D. A., Buss, T. N., Holmes, M. A., Anasetti, C., & Foote, J. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.2.1119 · Cited by 102
“However, CD80 and CD86 can also interact with CTLA4, a molecule structurally related to CD28 that is also found on T cells (8).”
Background
The contributions of T‐cell anergy to peripheral T‐cell tolerance
Lechler, R. I., Chai, J., Marelli‐Berg, F. M., & Lombardi, G. (2001) · Immunology · doi:10.1046/j.1365-2567.2001.01250.x · Cited by 98
Mechanisms of immune checkpoint inhibitor-mediated liver injury
Shojaie, L., Ali, M., Iorga, A., & Dara, L. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.10.003 · Cited by 98
Tumor-associated Tregs obstruct antitumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating CD8+ T cells
Noyes, D. R., Bag, A. K., Oseni, S. O., Semidey-Hurtado, J., Cen, L., Sarnaik, A. A., Sondak, V. K., & Adeegbe, D. O. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-004605 · Cited by 101
An alternate mechanism of glucocorticoid anti‐proliferative effect: promotion of a Th2 cytokine‐secreting profile
Almawi, W., Melemedjian, O., & Rieder, M. J. (1999) · Clinical Transplantation · doi:10.1034/j.1399-0012.1999.130501.x · Cited by 97
“The provision of co-stimulatory signals, imparted by cell-bound (17, 18) and secreted (19) accessory/co-stimulatory molecules, complement TcR/CD3 signals in augmenting T-cell activation (Fig.”
Background
Immunotherapy of cancers comes of age
Yousefi, H., Yuan, J. D., Keshavarz‐Fathi, M., Murphy, J. F., & Rezaei, N. (2017) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2017.1366315 · Cited by 97
Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy
Babamohamadi, M., Mohammadi, N., Faryadi, E., Haddadi, M., Merati, A., Ghobadinezhad, F., Amirian, R., Izadi, Z., & Hadjati, J. (2024) · Cell Death and Disease · doi:10.1038/s41419-023-06391-x · Cited by 104
CD59 molecule: A second ligand for CD2 in T cell adhesion
Deckert, M., Kubar, J., Zoccola, D., Bernard‐Pomier, G., Angelisová, P., Hořejšı́, V., & Bernard, A. (1992) · European Journal of Immunology · doi:10.1002/eji.1830221128 · Cited by 96
Advances in CTLA-4-Ig-mediated modulation of inflammatory cell and immune response activation in rheumatoid arthritis
Cutolo, M., & Nadler, S. G. (2013) · Autoimmunity Reviews · doi:10.1016/j.autrev.2013.01.001 · Cited by 95
“Elucidation of these co-stimulatory pathways led to the development of the CD28:CD80/86 signal as a therapeutic target for RA [20,21].”
Background
The Multifaceted Role of Th1, Th9, and Th17 Cells in Immune Checkpoint Inhibition Therapy
Lee, J., Lozano‐Ruiz, B., Yang, F. M., Fan, D. D., Shen, L., & González-Navajas, J. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.625667 · Cited by 102
“Like CD28, CTLA-4 binds to CD80 (B7-1) and CD86 (B7-2) molecules on APCs, but with much higher avidity than CD28 (17) and with opposite effect (15, 19).”
Background
Soluble CTLA-4 in autoimmune thyroid diseases: Relationship with clinical status and possible role in the immune response dysregulation
Saverino, D., Brizzolara, R., Simone, R., Chiappori, A., Milintenda-Floriani, F., Pesce, G., & Bagnasco, M. (2007) · Clinical Immunology · doi:10.1016/j.clim.2007.01.003 · Cited by 95
Lymphocyte populations and immune responses in CD5‐deficient mice
Tarakhovsky, A., Müller, W., & Rajewsky, K. (1994) · European Journal of Immunology · doi:10.1002/eji.1830240733 · Cited by 95
Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) Engagement Delivers an Inhibitory Signal through the Membrane-Proximal Region in the Absence of the Tyrosine Motif in the Cytoplasmic Tail
Nakaseko, C., Miyatake, S., Iida, T., Hara, S., Abe, R., Ohno, H., & Saito, T. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.6.765 · Cited by 95
“One of the mechanisms of suppression by CTLA-4 has been thought to be the competition of the ligand CD80/86 with CD28 (34, 35).”
Background
Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis
Garin, E. H., Reiser, J., Cara‐Fuentes, G., Wei, C., Matar, D., Wang, H., Alachkar, N., & Johnson, R. J. (2014) · Pediatric Nephrology · doi:10.1007/s00467-014-2957-6 · Cited by 94
“We therefore administered abatacept (CTLA4–IgG1), which is a fusion protein that comprises the extracellular domain of human CTLA-4 and an Fc fragment of human immunoglobulin G subclass 1 (IgG1) [18].”
Method
Checkpoint inhibitors and other novel immunotherapies for advanced renal cell carcinoma
Carlo, M. I., Voss, M. H., & Motzer, R. J. (2016) · Nature Reviews Urology · doi:10.1038/nrurol.2016.103 · Cited by 95
Vaccination response to tetanus toxoid and 23-valent pneumococcal vaccines following administration of a single dose of abatacept: a randomized, open-label, parallel group study in healthy subjects
Tay, L. K., León, F., Vratsanos, G., Raymond, R. H., & Corbo, M. (2007) · Arthritis Research & Therapy · doi:10.1186/ar2174 · Cited by 94
“Abatacept is the first in a class of agents for the treatment of RA that selectively modulates the CD80/CD86:CD28 co-stimulatory signal required for full T-cell activation [4].”
BackgroundInfluential
CTLA-4 is required for the induction of high dose oral tolerance
Samoilova, E. B. (1998) · International Immunology · doi:10.1093/intimm/10.4.491 · Cited by 94
Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab
Lau, K. H. V., Kumar, A., Yang, I. H., & Nowak, R. J. (2016) · Muscle & Nerve · doi:10.1002/mus.25141 · Cited by 93
“The first observation of T-cell inhibitory signaling in the regulation of T-cell tolerance came with the discovery of CTLA-4, which is a member of the B7:CD28 (CD, cluster of differentiation) family of costimulatory receptors.(8) The anti-CTLA-4 biologic, ipilimumab, found success for treatment of metastatic malignant…”
Background
Expression and functional properties of mouse B7/BB1 using a fusion protein between mouse CTLA4 and human gamma 1.
Lane, P. J. L., Gerhard, W., Hubele, S., Lanzavecchia, A., & McConnell, F. M. (1993) · PubMed Central · Cited by 93
Costimulation Blockade in Autoimmunity and Transplantation: The CD28 Pathway
Adams, A. B., Ford, M. L., & Larsen, C. P. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1601135 · Cited by 93
“To their surprise, CTLA-4-Ig not only bound to the B7 proteins, but it did so much more effectively than CD28 (18).”
Background
Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade
Tian, T., & Li, Z. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.731175 · Cited by 100
Physical Instability of a Therapeutic Fc Fusion Protein: Domain Contributions to Conformational and Colloidal Stability
Fast, J. L., Cordes, A. A., Carpenter, J. F., & Randolph, T. W. (2009) · Biochemistry · doi:10.1021/bi900853v · Cited by 92
Differential Requirement for CD80 and CD80/CD86-Dependent Costimulation in the Lung Immune Response to an Influenza Virus Infection
Lumsden, J. M., Roberts, J., Harris, N. L., Peach, R., & Ronchese, F. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.1.79 · Cited by 92
“The mAb L6-Ig, which has a human Fc region, was used as a control (12).”
Method
The Obesity Paradox in Cancer, Tumor Immunology, and Immunotherapy: Potential Therapeutic Implications in Triple Negative Breast Cancer
Naik, A., Monjazeb, A. M., & Decock, J. V. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01940 · Cited by 94
Time to dissect the autoimmune etiology of cancer antibody immunotherapy
Dougan, M. L., & Pietropaolo, M. (2020) · Journal of Clinical Investigation · doi:10.1172/jci131194 · Cited by 92
Expression of CTLA‐4 by Human Monocytes
Wang, X. ‐., Giscombe, R., Yan, Z., Heiden, T., Xu, D., & Lefvert, A. K. (2002) · Scandinavian Journal of Immunology · doi:10.1046/j.0300-9475.2001.01019.x · Cited by 90
T cell activation defect in hemodialysis patients: Evidence for a role of the B7/CD28 pathway
Girndt, M., Köhler, H., Schiedhelm-Weick, E., Büschenfelde, K. M. Z., & Fleischer, B. (1993) · Kidney International · doi:10.1038/ki.1993.252 · Cited by 91
Humanized Mouse Models of Rheumatoid Arthritis for Studies on Immunopathogenesis and Preclinical Testing of Cell-Based Therapies
Schinnerling, K., Rosas, C., Soto, L., Thomas, R., & Aguillón, J. C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00203 · Cited by 93
“Treatment of human cit-fibrinogen-immunized DR4 Tg mice with CTLA-4Ig fusion protein, a soluble form of the CTLA-4 receptor which inhibits T cell activation by competing with CD28 for binding to the costimulatory ligand CD80/CD86 (174), restrained the activation of cit-fibrinogen-specific T cell responses, and halted…”
Method
CTLA-4 regulates cell cycle progression during a primary immune response
Greenwald, R. J., Oosterwegel, M. A., van der Woude, D., Kubal, A., Mandelbrot, D. A., Boussiotis, V. A., & Sharpe, A. H. (2002) · European Journal of Immunology · doi:10.1002/1521-4141(200202)32:2 · Cited by 120
CTLA‐4, a Negative Regulator of T‐Lymphocyte Activation
Waterhouse, P. D., Marengère, L. E. M., Mittrücker, H., & Mak, T. W. (1996) · Immunological Reviews · doi:10.1111/j.1600-065x.1996.tb00925.x · Cited by 87
Roles of Epstein–Barr virus glycoproteins gp350 and gp25 in the infection of human epithelial cells
Maruo, S., Yang, L., & Takada, K. (2001) · Journal of General Virology · doi:10.1099/0022-1317-82-10-2373 · Cited by 89
“CTLA4Ig, which is known to bind to the B cell activation antigen B7 family (Linsley et al., 1991b), bound strongly to B cell lines but not to epithelial cell lines, as was expected.”
BackgroundMethod
B7 Costimulation Is Required for IL-5 and IL-13 Secretion by Bronchial Biopsy Tissue of Atopic Asthmatic Subjects in Response to Allergen Stimulation
Jaffar, Z. H., Roberts, K., Pandit, A., Linsley, P. S., Djukanović, R., & Holgate, S. T. (1999) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.20.1.3255 · Cited by 87
Self-citation
SKIN ALLOGRAFT REJECTION IN CD28-DEFICIENT MICE1
Kawai, K., Shahinian, A., Mak, T. W., & Ohashi, P. S. (1996) · Transplantation · doi:10.1097/00007890-199602150-00003 · Cited by 89

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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