{"doi":"10.4049/jimmunol.152.6.2686","title":"Costimulation of T lymphocytes with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 induces functional expression of CTLA-4, a second receptor for B7.","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>Costimulation by the CD28 ligand B7/BB1 plays an important role during T cell proliferation primarily by augmenting synthesis of IL-2 and other cytokines. Resting CD4+ T cells express CD28 but not CTLA-4 on their surface. Costimulation of T cells with ICAM-1 or VCAM-1 induced CTLA-4 expression and up-regulated CD28 expression. CD28 and CTLA-4 were independently distributed on the surface of activated T lymphoblasts. When co-immobilized with anti-TCR mAb both anti-CD28 and anti-CTLA-4 mAb augmented T cell proliferation. Although anti-CD28-mediated augmentation of T cell proliferation was stronger than that seen with anti-CTLA-4 mAb, together these two mAb caused supraadditive augmentation of T cell proliferation. The augmentation of the effects of anti-CD28 mAb by anti-CTLA-4 mAb was greater at low occupancy of CD28 by anti-CD28 mAb. Costimulation of CD28+ CTLA-4+ T cells with anti-CTLA-4 caused three- to fivefold increase in IL-2 production, whereas similar treatment with anti-CD28 caused &amp;gt; 40-fold increase. The costimulatory effect of B7 on primed T cells was partially inhibited by Fab anti-CD28 mAb. Anti-CTLA-4 mAb alone did not inhibit B7-induced response but caused modest increase in the inhibitory effect of anti-CD28 Fab. On integrin-mediated costimulation, Ag-specific CD4+ T cell lines also up-regulated their CTLA-4 expression, and proliferation of these cells was augmented by anti-CTLA-4 mAb. Unlike that of CD28, ligation of CTLA-4 alone failed to mobilize intracellular [Ca2+]. However, coligation of CTLA-4 and TCR induced stronger [Ca2+] response in Ag-specific T cell lines than that seen with TCR alone. These results suggest that integrin-costimulated T cells express CTLA-4 and can be costimulated via CTLA-4. Optimal development of various immune functions may involve combined costimulation via both CD28 and CTLA-4.</jats:p>","journal":"The Journal of Immunology","year":1994,"id":592630,"datarank":6.464138855168325,"base_score":4.499809670330265,"endowment":4.499809670330265,"self_citation_contribution":0.6749714505495399,"citation_network_contribution":5.789167404618785,"self_endowment_contribution":0.6749714505495399,"citer_contribution":5.789167404618785,"corpus_percentile":null,"corpus_rank":null,"citation_count":89,"citer_count":87,"citers_with_citation_signal":83,"citers_with_endowment":83,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1516560,"name":"K Klussman","orcid":null,"position":1,"is_corresponding":false},{"id":1516561,"name":"G Leytze","orcid":null,"position":2,"is_corresponding":false},{"id":1516562,"name":"S Myrdal","orcid":null,"position":3,"is_corresponding":false},{"id":1516563,"name":"A Aruffo","orcid":null,"position":4,"is_corresponding":false},{"id":1516564,"name":"J A Ledbetter","orcid":null,"position":5,"is_corresponding":false},{"id":1516565,"name":"P S Linsley","orcid":null,"position":6,"is_corresponding":false},{"id":1516559,"name":"N K Damle","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Costimulation of T lymphocytes with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 induces functional expression of CTLA-4, a second receptor for B7.","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>Costimulation by the CD28 ligand B7/BB1 plays an important role during T cell proliferation primarily by augmenting synthesis of IL-2 and other cytokines. Resting CD4+ T cells express CD28 but not CTLA-4 on their surface. Costimulation of T cells with ICAM-1 or VCAM-1 induced CTLA-4 expression and up-regulated CD28 expression. CD28 and CTLA-4 were independently distributed on the surface of activated T lymphoblasts. When co-immobilized with anti-TCR mAb both anti-CD28 and anti-CTLA-4 mAb augmented T cell proliferation. Although anti-CD28-mediated augmentation of T cell proliferation was stronger than that seen with anti-CTLA-4 mAb, together these two mAb caused supraadditive augmentation of T cell proliferation. The augmentation of the effects of anti-CD28 mAb by anti-CTLA-4 mAb was greater at low occupancy of CD28 by anti-CD28 mAb. Costimulation of CD28+ CTLA-4+ T cells with anti-CTLA-4 caused three- to fivefold increase in IL-2 production, whereas similar treatment with anti-CD28 caused &amp;gt; 40-fold increase. The costimulatory effect of B7 on primed T cells was partially inhibited by Fab anti-CD28 mAb. Anti-CTLA-4 mAb alone did not inhibit B7-induced response but caused modest increase in the inhibitory effect of anti-CD28 Fab. On integrin-mediated costimulation, Ag-specific CD4+ T cell lines also up-regulated their CTLA-4 expression, and proliferation of these cells was augmented by anti-CTLA-4 mAb. Unlike that of CD28, ligation of CTLA-4 alone failed to mobilize intracellular [Ca2+]. However, coligation of CTLA-4 and TCR induced stronger [Ca2+] response in Ag-specific T cell lines than that seen with TCR alone. These results suggest that integrin-costimulated T cells express CTLA-4 and can be costimulated via CTLA-4. Optimal development of various immune functions may involve combined costimulation via both CD28 and CTLA-4.</jats:p>","is_dataset_classified":null,"base_score":4.499809670330265,"endowment":4.499809670330265,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"7511623","pmcid":null,"openalex_id":"https://openalex.org/W1522355179","authors":[],"funders":[],"total_grants":0,"fwci":4.4931,"citation_percentile":0.9601927,"influential_citations":0,"citation_trend":[{"year":2014,"count":1},{"year":2015,"count":2},{"year":2016,"count":2},{"year":2020,"count":1},{"year":2021,"count":2},{"year":2023,"count":1}],"oa_status":"bronze","license":"https://academic.oup.com/pages/standard-publication-reuse-rights","oa_locations":[{"url":"https://journals.aai.org/jimmunol/article-pdf/152/6/2686/1066798/2686.pdf","host_type":"journal"},{"url":"https://journals.aai.org/jimmunol/article-pdf/152/6/2686/1066798/2686.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/jimmunol/article-pdf/152/6/2686/62221322/2686.pdf","host_type":"publisher"},{"url":"https://doi.org/10.4049/jimmunol.152.6.2686","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/7511623","host_type":"repository"}],"fields_of_study":["Cancer Immunotherapy and Biomarkers","T-cell and B-cell Immunology","Immunotherapy and Immune Responses"],"mesh_terms":["Abatacept","Antigens, Differentiation","Calcium","Humans","Lymphocyte Activation","T-Lymphocytes","Antigens, CD","Cell Adhesion Molecules","Integrins","Cytokines","Receptors, Antigen, T-Cell, alpha-beta","CD28 Antigens","B7-1 Antigen","Immunoconjugates","Intercellular Adhesion Molecule-1","Vascular Cell Adhesion Molecule-1","CTLA-4 Antigen"],"keywords":["CD28","T cell","CTLA-4","Cell biology","Chemistry","Molecular biology","Cytotoxic T cell","IL-2 receptor","Biology","Immunology","In vitro","Biochemistry","Immune system"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-26T14:35:06.207545Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}