title: Functional heterogeneity of vaccine-induced CD8(+) T cells.
abstract: The functional status of circulating vaccine-induced, tumor-specific T cells has been questioned to explain their paradoxical inability to inhibit tumor growth. We enumerated with HLA-A*0201/peptide tetramers (tHLA) vaccine-elicited CD8(+) T cell precursor frequency among PBMC in 13 patients with melanoma undergoing vaccination with the HLA-A*0201-associated gp100:209-217(210 M) epitope. T cell precursor frequency increased from undetectable to 12,400 +/- 3,600 x 10(6) CD8(+) T cells after vaccination and appeared heterogeneous according to previously described functional subtypes: CD45RA(+)CD27(+) (14 +/- 2.6% of tHLA-staining T cells), naive; CD45RA(-)CD27(+) (14 +/- 3.2%), memory; CD45RA(+)CD27(-) (43 +/- 6%), effector; and CD45RA(-)CD27(-) (30 +/- 4.1%), memory/effector. The majority of tHLA(+)CD8(+) T cells displayed an effector, CD27(-) phenotype (73%). However, few expressed perforin (17%). Epitope-specific in vitro stimulation (IVS) followed by 10-day expansion in IL-2 reversed this phenotype by increasing the number of perforin(+) (84 +/- 3.6%; by paired t test, p < 0.001) and CD27(+) (from 28 to 67%; by paired t test, p = 0.01) tHLA(+) T cells. This conversion probably represented a change in the functional status of tHLA(+) T cells rather than a preferential expansion of a CD27(+) (naive and/or memory) PBMC, because it was reproduced after IVS of a T cell clone bearing a classic effector phenotype (CD45RA(+)CD27(-)). These findings suggest that circulating vaccine-elicited T cells are not as functionally active as inferred by characterization of IVS-induced CTL. In addition, CD45RA/CD27 expression may be more informative about the status of activation of circulating T cells than their status of differentiation.
authors.affiliation: Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, and Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Vladia
authors.initials: V
authors.lastname: Monsurrò
authors.forename: Dirk
authors.initials: D
authors.lastname: Nagorsen
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Maurizio
authors.initials: M
authors.lastname: Provenzano
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007376:Interleukin-2 / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008562:Membrane Glycoproteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D014407:Tumor Cells, Cultured; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D058951:gp100 Melanoma Antigen
chemical_list: D019496:Cancer Vaccines; D007376:Interleukin-2; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D058951:gp100 Melanoma Antigen; D017493:Leukocyte Common Antigens