IL-12 controls cytotoxicity of a novel subset of self-antigen-specific human CD28+ cytolytic T cells.
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.
Barbey
Catherine
C
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Centre Hospitalier Universitaire Vaudois, Avenue Pierre-Decker 4, CH-1005 Lausanne, Switzerland.
Baumgaertner
Petra
P
Devevre
Estelle
E
Rubio-Godoy
Verena
V
Derre
Laurent
L
Bricard
Gabriel
G
Guillaume
Philippe
P
Luescher
Immanuel F
IF
Liénard
Danielle
D
Cerottini
Jean-Charles
JC
Romero
Pedro
P
Rufer
Nathalie
N
Speiser
Daniel E
DE
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
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