title: CD8alpha/alpha homodimers fail to function as co-receptor for a CD8-dependent TCR.
abstract: In this study, we have started to dissect the molecular basis of CD8 dependence of a high and low avidity CTL clone specific for the same peptide epitope. Using anti-CD8alpha and anti-CD8beta antibodies, we found that cytotoxicity and IFN-gamma production by high but not by low avidity CTL was strongly CD8 dependent. We isolated the TCR genes of both types of CTL clones and used retroviral gene transfer to analyse the function of these TCR in primary T cells of wild-type and CD8beta-deficient mice. Both TCR triggered antigen-specific killing in wild-type T cells, and blocking experiments showed that CD8 dependence/independence co-transferred with the TCR into primary T cells, indicating that it was dictated by the TCR itself. Gene transfer experiments into CD8beta-deficient T cells revealed that only the TCR derived from the CD8-independent CTL clone elicited antigen-specific cytotoxicity, while the CD8-dependent TCR was non-functional in the absence of the CD8beta-chain. These data indicate a striking difference between CD8alpha/beta heterodimers and CD8alpha/alpha homodimers as only the former were able to provide co-receptor function for the CD8-dependent TCR.
authors.affiliation: Department of Immunology and Molecular Pathology, University College London, London, UK.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: McNicol
authors.forename: Gavin
authors.initials: G
authors.lastname: Bendle
authors.forename: Angelika
authors.initials: A
authors.lastname: Holler
authors.forename: Theres
authors.initials: T
authors.lastname: Matjeka
authors.forename: Emma
authors.initials: E
authors.lastname: Dalton
authors.forename: Lorna
authors.initials: L
authors.lastname: Rettig
authors.forename: Rose
authors.initials: R
authors.lastname: Zamoyska
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.forename: Shao-An
authors.initials: SA
authors.lastname: Xue
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Stauss
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology; D021122:Protein Subunits / Q000276:immunology / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; C477867:CD8beta antigen; D010455:Peptides; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015847:Interleukin-4; D007371:Interferon-gamma; D051736:Proto-Oncogene Proteins c-mdm2