title: Antigen-presenting cells containing multiple costimulatory molecules promote activation and expansion of human antigen-specific memory CD8+ T cells.
abstract: We have previously demonstrated that multiple immunizations with vector-based vaccines containing transgenes for tumor Ags and a triad of costimulatory molecules (TRICOM) enhance the expansion and functional avidity of Ag-specific memory CD8(+) T cells in a mouse model. However, the effect of enhanced costimulation on human memory CD8(+) T cells is still unclear. The study reported here was an in vitro investigation of the proliferation and function of CEA-specific human memory CD8(+) T cells following enhanced costimulation. Our results demonstrated that TRICOM costimulation enhanced production of multiple cytokines and expansion of CEA-specific memory CD8(+) T cells. The lytic capacity of memory CTLs toward CEA(+) tumors was also significantly enhanced. IL-2R alpha (CD25) was upregulated dramatically following APC-TRICOM stimulation, suggesting that the enhanced expansion of memory CD8(+) T cells may be mediated by increased expression of IL-2R on memory T cells. The enhanced cytokine production and proliferation following TRICOM signaling was completely blocked by the combination of neutralizing Abs against B7-1, ICAM-1, and LFA-3, the costimulatory molecules comprising TRICOM. No difference in T-cell apoptosis was observed between APC-TRICOM and APC-wild-type groups, as determined by annexin V, Bcl-2, and active caspase-3 staining. Results indicated that enhanced costimulation greatly expanded human CEA-specific CD8(+) T cells and enhanced T-cell function, without inducing increased apoptosis of CEA-specific memory CD8(+) T cells.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Bethesda, MD 20892, USA.
authors.forename: Sixun
authors.initials: S
authors.lastname: Yang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D018968:CD58 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D019076:Transgenes
chemical_list: D018122:B7-1 Antigen; D018968:CD58 Antigens; D002272:Carcinoembryonic Antigen; D016207:Cytokines; D018799:Intercellular Adhesion Molecule-1