title: IL-12 controls cytotoxicity of a novel subset of self-antigen-specific human CD28+ cytolytic T cells.
abstract: Activated CD8 T cells develop cytotoxicity against autologous cells bearing foreign Ags and self/tumor Ags. However, self-specific cytolysis needs to be kept under control to avoid overwhelming immunopathology. After peptide vaccination of melanoma patients, we studied molecular and functional properties of T cell subsets specific for the self/tumor Ag Melan-A/MART-1. Ex vivo analysis revealed three Ag-specific effector memory (EM) populations, as follows: CD28-negative EM (EM28(-)) T cells strongly expressing granzyme/perforin, and two EM28(+) subsets, one with high and the other with low level expression of these cytotoxic proteins. For further functional characterization, we generated 117 stable CD8 T cell clones by ex vivo flow cytometry-based sorting of these subsets. All EM28(-)-derived clones lysed target cells with high efficacy. In contrast, EM28(+)-derived clones were heterogenous, and could be classified in two groups, one with high and the other with low killing capacity, correlating with granzyme/perforin expression. High and low killer phenotypes remained surprisingly stable for several months. However, strongly increased granzyme expression and cytotoxicity were observed after exposure to IL-12. Thus, the data reveal a newly identified subset of CD28(+) conditional killer T cells. Because CD28 can mediate strong costimulatory signals, tight cytotoxicity control, as shown in this study through IL-12, may be particularly important for subsets of T cells expressing CD28.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Centre Hospitalier Universitaire Vaudois, Avenue Pierre-Decker 4, CH-1005 Lausanne, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Barbey
authors.forename: Petra
authors.initials: P
authors.lastname: Baumgaertner
authors.forename: Estelle
authors.initials: E
authors.lastname: Devevre
authors.forename: Verena
authors.initials: V
authors.lastname: Rubio-Godoy
authors.forename: Laurent
authors.initials: L
authors.lastname: Derre
authors.forename: Gabriel
authors.initials: G
authors.lastname: Bricard
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
authors.forename: Danielle
authors.initials: D
authors.lastname: Liénard
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Cerottini
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D018106:CD28 Antigens / Q000096:biosynthesis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002999:Clone Cells; D005260:Female; D053804:Granzymes / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D018664:Interleukin-12 / Q000494:pharmacology*; D007519:Isoantigens / Q000008:administration & dosage / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000096:biosynthesis / Q000276:immunology; D013997:Time Factors; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D007519:Isoantigens; C415186:MART-1 antigen (27-35), Leu(28)-beta-HIle(30)-; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D018664:Interleukin-12; D053804:Granzymes