title: Cooperation of human tumor-reactive CD4+ and CD8+ T cells after redirection of their specificity by a high-affinity p53A2.1-specific TCR.
abstract: Efficient immune attack of malignant disease requires the concerted action of both CD8+ CTL and CD4+ Th cells. We used human leukocyte antigen (HLA)-A*0201 (A2.1) transgenic mice, in which the mouse CD8 molecule cannot efficiently interact with the alpha3 domain of A2.1, to generate a high-affinity, CD8-independent T cell receptor (TCR) specific for a commonly expressed, tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the human p53 tumor suppressor protein. Retroviral expression of this CD8-independent, p53-specific TCR into human T cells imparted the CD8+ T lymphocytes with broad tumor-specific CTL activity and turned CD4+ T cells into potent tumor-reactive, p53A2.1-specific Th cells. Both T cell subsets were cooperative and interacted synergistically with dendritic cell intermediates and tumor targets. The intentional redirection of both CD4+ Th cells and CD8+ CTL by the same high-affinity, CD8-independent, tumor-specific TCR could provide the basis for novel broad-spectrum cancer immunotherapeutics.
authors.affiliation: Department of Hematology and Oncology, Johannes Gutenberg University, 55101 Mainz, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kuball
authors.forename: Frank W
authors.initials: FW
authors.lastname: Schmitz
authors.forename: Ralf-Holger
authors.initials: RH
authors.lastname: Voss
authors.forename: Edite Antunes
authors.initials: EA
authors.lastname: Ferreira
authors.forename: Renate
authors.initials: R
authors.lastname: Engel
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Susanne
authors.initials: S
authors.lastname: Strand
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Linda A
authors.initials: LA
authors.lastname: Sherman
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003001:Cloning, Molecular; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53