title: Tumor antigen-specific T-cells are Present in the CD8alphaalpha+ T-cell effector-memory pool.
abstract: CD8+ T-cell memory formation has recently been demonstrated to be associated with CD8alphaalpha homodimer expression by T-cells in mice. Up to now, the knowledge about the clinical significance of CD8alphaalpha+ T-cells in humans is limited. We assessed in longitudinally collected blood samples from patients with melanoma, who underwent a peptide-based vaccination, the role of CD8alphaalpha+ T-cells in tumor-specific cellular immune responses. Phenotypic analysis showed that the expression of CD8alphaalpha+ by T-cells was stable over time and associated with a CD45RA+/-CCR7- effector-memory profile. Melan-A/MART-1-specific T-cells were identified in the CD8alphaalpha+ T-cell compartment by tetramer technology. Detection of intracellular cytokine production (interleukin-2, interferon-gamma, and tumor necrosis factor-alpha) upon phorbol 12-myristate 13-acetate-ionomycin stimulation in CD8alphaalpha+ and CD8alphabeta+ T-cells revealed that CD8alphaalpha+ T-cells show a unique cytokine production pattern (tumor necrosis factor-alpha and interferon-gamma production) as compared with CD8alphabeta+ T-cells. T-cell receptor-CDR3 length analysis revealed that Melan-A/MART-1-specific CD8alphaalpha+ T-cells showed a similar T-cell receptor-repertoire as compared with Melan-A/MART-1-specific CD8alphabeta+ T-cells. Our results show that CD8alphaalpha+ T-cells represent a compartment of CD45RA+/- effector-memory cells in the peripheral circulation of patients with melanoma and suggest that CD8alphaalpha T-cells may originate from CD8+ T-cells that have down-regulated the expression of the CD8beta chain. CD8alphaalpha+ and tetramer-specific T-cells may represent a valuable marker to gauge long-term antigen-specific T-cell memory.
authors.affiliation: Microbiology and Tumor Cell Biology Center, Karolinska Institute, Nobels Väg 18 and SMI, Solna, Sweden.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Magalhaes
authors.forename: Nalini Kumar
authors.initials: NK
authors.lastname: Vudattu
authors.forename: Elke
authors.initials: E
authors.lastname: Jäger
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Maeurer
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D015415:Biomarkers / Q000097:blood*; D016827:CD8 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D019496:Cancer Vaccines; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D007156:Immunologic Memory; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D037182:T-Cell Antigen Receptor Specificity; D022223:Vaccines, Subunit / Q000276:immunology / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D019496:Cancer Vaccines; D016207:Cytokines; D022223:Vaccines, Subunit; D017493:Leukocyte Common Antigens