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
Prevention of renal damage in murine lupus nephritis by CTLA‐4Ig and cyclophosphamide
Cunnane, G., Chan, O. T. M., Cassafer, G., Brindis, S. L., Kaufman, E. A., Yen, T. S. B., & Daikh, D. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20147 · Cited by 53
Staying Alive: T Cell Costimulation, CD28, and Bcl-xL
Watts, T. H. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1090085 · Cited by 57
“Although not all immune responses were found to be CD28 dependent (13), studies showing that CD28–B7 interactions could costimulate T cells and prevent T cell clonal anergy, as well as the dramatic inhibitory effects of B7 blockade by CTLA-4-Ig in vivo, cemented the role of CD28 as a key receptor for signal 2 for T ly…”
Influential
Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab
Bjoern, J., Iversen, T. Z., Nitschke, N. J., Andersen, M. H., & Svane, I. M. (2016) · Cytotherapy · doi:10.1016/j.jcyt.2016.05.010 · Cited by 53
“2 (CD80 and CD86, respectively), expressed on antigen presenting cells, CTLA-4 inhibits T-cell function and proliferation [11].”
Background
Metastatic melanoma and immunotherapy
Herzberg, B., & Fisher, D. E. (2016) · Clinical Immunology · doi:10.1016/j.clim.2016.07.006 · Cited by 58
“CTLA-4, a molecule which is found on the T-cell surface, can bind to B7-1 and B7-2 with much higher affinity than CD28, and, when bound, inhibits the T-cell response, acting as a balancing inhibitory signal [38, 39].”
Background
Survival of Lung Adenocarcinoma Patients Predicted from Expression of PD-L1, Galectin-9, and XAGE1 (GAGED2a) on Tumor Cells and Tumor-Infiltrating T Cells
Ohue, Y., Kurose, K., Nozawa, R., Isobe, M., Nishio, Y., Tanaka, T., Doki, Y., Hori, T., Fukuoka, J., Oka, M., et al. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0266 · Cited by 53
“Each of these proteins contributes to the dysfunction of effector T cells in the tumor microenvironment when bound by their ligands; CD80 (B7-1) or CD86 (B7-2) for CTLA-4 (9, 10), PD-L1 (B7-H1) or PD-L2 (B7DC; refs.”
Background
Integration of radiation and immunotherapy in breast cancer - Treatment implications
Ye, J. C., & Formenti, S. C. (2018) · The Breast · doi:10.1016/j.breast.2017.12.005 · Cited by 55
DNA vaccines in sheep: CTLA-4 mediated targeting and CpG motifs enhance immunogenicity in a DNA prime/protein boost strategy
Kennedy, N. J., Spithill, T. W., Tennent, J. M., Wood, P. R., & Piedrafita, D. M. (2005) · Vaccine · doi:10.1016/j.vaccine.2005.08.076 · Cited by 53
“CTLA-4 present on activated T-cells binds with high affinity to the B7 (CD80/86) molecules [5] on the”
Background
CD40/CD40L Interaction is Essential for the Induction of EAE in the Absence of CD28-Mediated Co-stimulation
Girvin, A. M., Canto, M. C. D., & Miller, S. D. (2002) · Journal of Autoimmunity · doi:10.1006/jaut.2001.0573 · Cited by 53
CTLA-4 downregulates epitope spreading and mediates remission in relapsing experimental autoimmune encephalomyelitis
Karandikar, N. J., Eagar, T. N., Vanderlugt, C. L., Bluestone, J. A., & Miller, S. D. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(00)00322-2 · Cited by 53
“: 11-312-503-7674; fax: 11-312-503- CTLA-4 (CD152), a homologue of CD28, that binds B7 1339. molecules with higher affinity (Linsley et al., 1991;E-mail address: s-d-miller@nwu.edu (S.D. Miller).”
Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors
Roy, D., Gilmour, C., Patnaik, S., & Wang, L. L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1264327 · Cited by 53
Long Noncoding RNAs Control the Modulation of Immune Checkpoint Molecules in Cancer
Xu, S., Wang, Q., Kang, Y., Liu, J., Yin, Y., Liu, L., Wu, H., Li, S., Sui, S., Shen, M., et al. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0696 · Cited by 52
Immune checkpoint inhibitors for the treatment of melanoma
Sabbatino, F., Liguori, L., Pepe, S., & Ferrone, S. (2022) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2038132 · Cited by 56
“CTLA4 (also known as CD152) is a receptor that plays a crucial role in the regulation of T cell activity [11,12] by mediating a coinhibitory signal through its interaction with B7 molecules on”
Background
Trends in Modern Drug Discovery
Eder, J., & Herrling, P. L. (2015) · Handbook of experimental pharmacology · doi:10.1007/164_2015_20 · Cited by 56
Future prospects in biologic therapy for systemic lupus erythematosus
Stohl, W. (2013) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2013.136 · Cited by 54
Recent Advances in Polymeric Nanomedicines for Cancer Immunotherapy
Lee, E. S., Shin, J. M., Son, S., Ko, H., Um, W., Song, S. H., Lee, J. A., & Park, J. H. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201801320 · Cited by 53
T cell costimulation, checkpoint inhibitors and anti-tumor therapy
Nandi, D., Pathak, S., Verma, T., Singh, M., Chattopadhyay, A., Thakur, S., Raghavan, A., Gokhroo, A., & Vijayamahantesh, V. (2020) · Journal of Biosciences · doi:10.1007/s12038-020-0020-2 · Cited by 58
Molecular mechanisms of immunity in corneal allotransplantation and xenotransplantation
Qian, Y., & Dana, M. R. (2001) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399401003246 · Cited by 51
Development of Immune Functions Related to Allergic Mechanisms in Young Children
Koning, H., Baert, M. R. M., Oranje, A. P., Savelkoul, H. F. J., & Neijens, H. J. (1996) · Pediatric Research · doi:10.1203/00006450-199609000-00001 · Cited by 52
Itk Negatively Regulates Induction of T Cell Proliferation by CD28 Costimulation
Liao, X. C., Fournier, S., Killeen, N. P., Weiss, A., Allison, J. P., & Littman, D. R. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.2.221 · Cited by 52
Bacterial Pathogens Induce Abscess Formation by CD4+T-Cell Activation via the CD28–B7-2 Costimulatory Pathway
Tzianabos, A. O., Chandraker, A. K., Kalka-Moll, W. M., Stingele, F., Dong, V. M., Finberg, R. W., Peach, R., & Sayegh, M. H. (2000) · Infection and Immunity · doi:10.1128/iai.68.12.6650-6655.2000 · Cited by 52
“The fusion protein CTLA4Ig contains the extracellular domain of CTLA4 (a homologue of CD28) fused to the human immunoglobulin G1 (IgG1) heavy chain (17) and functions to prevent engagement of the CD28-B7 axis.”
Background
HLA-DRB1 risk alleles for RA are associated with differential clinical responsiveness to abatacept and adalimumab: data from a head-to-head, randomized, single-blind study in autoantibody-positive early RA
Rigby, W. F. C., Buckner, J. H., Bridges, S. L., Nys, M., Gao, S., Polinsky, M. S., Ray, N., & Bykerk, V. P. (2021) · Arthritis Research & Therapy · doi:10.1186/s13075-021-02607-7 · Cited by 51
Advances in mouse models of prostate cancer
Ahmad, I., Sansom, O. J., & Leung, H. Y. (2008) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399408000689 · Cited by 50
Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy
Kean, L. S., Turka, L. A., & Blazar, B. R. (2017) · Immunological Reviews · doi:10.1111/imr.12523 · Cited by 50
B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes
Linsley, P. S., Greenbaum, C. J., Speake, C., Long, S. A., & Dufort, M. J. (2019) · JCI Insight · doi:10.1172/jci.insight.126136 · Cited by 51
Self-citation
Check Point Inhibitors and Their Role in Immunosuppression in Sepsis
Wakeley, M. E., Gray, C. C., Monaghan, S. F., Heffernan, D. S., & Ayala, A. (2019) · Critical Care Clinics · doi:10.1016/j.ccc.2019.08.006 · Cited by 58
Expression of the co‐stimulatory molecule B7 on melanoma cells
Hersey, P., Si, Z., Smith, M. J., & Thomas, W. D. (1994) · International Journal of Cancer · doi:10.1002/ijc.2910580413 · Cited by 54
Abnormalities of B cells and dendritic cells in SAMP1 mice
Haruna, H., Inaba, M., Inaba, K., Taketani, S., Sugiura, K., Fukuba, Y., Doi, H., Toki, J., Tokunaga, R., & Ikehara, S. (1995) · European Journal of Immunology · doi:10.1002/eji.1830250528 · Cited by 51
Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication
Garber, D. A., Silvestri, G., Barry, A. P., Fedanov, A., Kozyr, N. L., McClure, H. M., Montefiori, D. C., Larsen, C. P., Altman, J. D., Staprans, S. I., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19442 · Cited by 51
“CTLA4-Ig (17) and anti-CD40L mAb block CD28-CD80/86 and CD40-CD40L lymphocyte-signaling”
Background
Mutational analysis and an alternatively spliced product of B7 defines its CD28/CTLA4-binding site on immunoglobulin C-like domain.
Guo, Y., Wu, Y., Zhao, M., Kong, X. P., & Liu, Y. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.181.4.1345 · Cited by 51
Abatacept in the treatment of rheumatoid arthritis
Buch, M. H., Vital, E. M. J., & Emery, P. (2008) · Arthritis Research & Therapy · doi:10.1186/ar2416 · Cited by 51
Antibody therapies for melanoma: New and emerging opportunities to activate immunity (Review)
Malas, S., Harrasser, M., Lacy, K. E., & Karagiannis, S. N. (2014) · Oncology Reports · doi:10.3892/or.2014.3275 · Cited by 50
“The cytotoxic T-lymphocyte antigen-4, CTLA4, expressed on the surface of activated T lymphocytes, acts as an inhibitory molecule of T cell activation by competing with CD28 for binding to the co-stimulatory B7 family members on antigen-presenting cells (60,61).”
Background
Melanoma: tumor microenvironment and new treatments
Bianchi, M. G., Junior, P. F. G.-B., & Neto, C. F. (2017) · Anais Brasileiros de Dermatologia · doi:10.1590/abd1806-4841.20176183 · Cited by 51
Primary Structure and Functional Characterization of a Soluble, Alternatively Spliced Form of B7-1
Faas, S. J., Giannoni, M. A., Mickle, A. P., Kiesecker, C. L., Reed, D. J., Wu, D., Fodor, W. L., Mueller, J. P., Matis, L. A., & Rother, R. P. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.12.6340 · Cited by 49
Targeting T cell costimulation in autoimmune disease
Racke, M. K., & Stuart, R. W. (2002) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.6.3.275 · Cited by 51
“Once bound, phosphatase activity is increased and a dramatic drop in IL-2 production and a decrease in T cell proliferation is observed [38-42].”
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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