ArticleThe Journal of experimental medicine1994
Complementarity determining region 1 (CDR1)- and CDR3-analogous regions in CTLA-4 and CD28 determine the binding to B7-1.
Article in The Journal of experimental medicine, 1994. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 1 of them a synthesis that pooled it.
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Who cites it
68 citing papers in PubMed, 1 synthesis or guideline pooled it, 246 citations in OpenAlex.
- In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways.Frontiers in immunology · 2022Pooled it
- Article
- Multifocal HPV16-positive squamous cell carcinomas in CTLA-4 haploinsufficiency: expanding the spectrum of virus-associated malignancies.Immunologic research · 2026Article
- Inducible T-Cell Co-Stimulator (ICOS) and ICOS Ligand: Dealing With a Two-Faced Cancer Immunoregulatory System.Cancer medicine · 2026Review
- Xenotransplantation: Promises and Perils.Annual review of medicine · 2026Review
- CD28 and ICOS in immune regulation: Structural insights and therapeutic targeting.Bioorganic & medicinal chemistry letters · 2025Review
- Article
- Moniezia benedeni infection promoting ICOSBMC veterinary research · 2025Article
- Post-translational modifications of immune checkpoints: unlocking new potentials in cancer immunotherapy.Experimental hematology & oncology · 2025Review
- Costimulatory receptors in the channel catfish: CD28 family members and their ligands.Immunogenetics · 2024Article
- Extraordinary diversity of the CD28/CTLA4 family across jawed vertebrates.Frontiers in immunology · 2024Article
- Granulocyte-Macrophage Colony-Stimulating Factor Influence on Soluble and Membrane-Bound ICOS in Combination with Immune Checkpoint Blockade.Cancer immunology research · 2023Article
- Immunotherapy in Prostate Cancer: State of Art and New Therapeutic Perspectives.Current oncology (Toronto, Ont.) · 2023Review
- CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer.Cell death & disease · 2023Article
- T cell co-stimulatory and co-inhibitory pathways in atopic dermatitis.Frontiers in immunology · 2023Review
- The Immunotherapy and Immunosuppressive Signaling in Therapy-Resistant Prostate Cancer.Biomedicines · 2022Review
- The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity.Nature communications · 2022Article
- Delivery of antigen to porcine dendritic cells by fusing antigen with porcine dendritic cells targeting peptide.Frontiers in immunology · 2022Article
- Insights Into the Host Contribution of Endocrine Associated Immune-Related Adverse Events to Immune Checkpoint Inhibition Therapy.Frontiers in oncology · 2022Review
- Peptide Blocking CTLA-4 and B7-1 Interaction.Molecules (Basel, Switzerland) · 2021Article
8 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
T cell surface receptors CD28 and CTLA-4 are homologous members of the immunoglobulin superfamily (IgSF), each comprising a single V-like extracellular domain. CD28 and CTLA-4 bind to the B7-1 and B7-2 counter-receptors on antigen presenting cells (APCs), thereby triggering a costimulatory pathway important for optimal T cell activation in vitro and in vivo. Soluble forms of CD28 and CTLA-4 in which the V-like extracellular domains were fused to Ig constant domains (CD28Ig and CTLA4Ig), have been used to study their interactions with B7-1 and B7-2, with CTLA4Ig binding B7-1 more strongly than CD28Ig (approximately 20-fold higher avidity). We have now, by site-specific and homologue mutagenesis, identified regions in CTLA4Ig important for strong binding to B7-1. A hexapeptide motif (MYPPPY) in the complementarity determining region 3 (CDR3)-like region is fully conserved in all CD28 and CTLA-4 family members. Alanine scanning mutagenesis through the motif in CTLA4Ig and at selected residues in CD28Ig reduced or abolished binding to B7-1. Chimeric molecules HS4, HS4-A, and HS4-B were constructed in which CDR3-like regions of CTLA-4, COOH-terminally extended to include nonconserved residues, were grafted onto CD28Ig. These homologue mutants showed stronger binding to B7-1 than did CD28Ig. Grafting of the CDR1-like region of CTLA-4, which is not conserved in CD28 and is predicted to be spatially adjacent to CDR3, into HS4 and HS4-A, resulted in chimeric molecules (HS7 and HS8) which bound B7-1 even better. Inclusion of the CDR2-like domain of CTLA-4 into HS7 and HS8 did not further increase binding. Thus, the MYPPPY motifs of CTLA4Ig and CD28Ig are important for their binding to B7-1, but the increased strength of this binding by CTLA4Ig is mediated by nonconserved residues in the CDR1- and CDR3-analogous regions.
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