title: Activated human gammadelta T cells as stimulators of specific CD8+ T-cell responses to subdominant Epstein Barr virus epitopes: potential for immunotherapy of cancer.
abstract: The efficacy of current cancer vaccines is limited by the functional heterogeneity and poor availability and expansion of professional antigen-presenting cells (APCs). Besides their potent innate effector properties, gammadelta T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human gammadelta T cells to induce expansion of virus-specific T cells to Epstein Barr virus (EBV) antigens. Aminobisphosphonate-stimulated human peripheral blood-derived gammadelta T cells (Vgamma2+Vdelta2+) acquired a dual phenotype characteristic for both APCs and effector memory T cells. Coincubation of activated gammadelta T cells pulsed with human leukocyte antigen-restricted epitopes of either the highly stimulatory EBV lytic cycle antigen Bam H1 Z fragment leftward open reading frame or the tumor-associated latent EBV antigen latent membrane protein 2a (LMP2a) with autologous peripheral blood lymphocytes induced selective expansion of peptide-specific, fully functional CD3CD8 cytolytic effector memory T cells. Furthermore, gammadelta T APCs efficiently processed and presented endogenous antigen, as demonstrated by the capacity of LMP2a gene-transduced gammadelta T cells to induce expansion of T cells with broad specificity for various LMP2a peptides. The capacity of autologous gammadelta T cells to induce LMP2a-specific autologous cytotoxic T lymphocytes was confirmed in 2 patients with Hodgkin lymphoma. In summary, bisphosphonate-activated human gammadelta T cells stimulate expansion of cytotoxic effector T cells specific for both subdominant and dominant viral epitopes and thus show promise as a novel source of efficient APCs for immunotherapy of viral and malignant disease.
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer-Street 33, Munster D-48149, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Landmeier
authors.forename: Bianca
authors.initials: B
authors.lastname: Altvater
authors.forename: Sibylle
authors.initials: S
authors.lastname: Pscherer
authors.forename: Heribert
authors.initials: H
authors.lastname: Juergens
authors.forename: Lena
authors.initials: L
authors.lastname: Varnholt
authors.forename: Anna
authors.initials: A
authors.lastname: Hansmeier
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
authors.forename: Andreas
authors.initials: A
authors.lastname: Moosmann
authors.forename: Guido
authors.initials: G
authors.lastname: Bisping
authors.forename: Claudia
authors.initials: C
authors.lastname: Rossig
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology / Q000821:virology; D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000628:therapy*; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007167:Immunotherapy; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D000077211:Zoledronic Acid
chemical_list: D000956:Antigens, Viral; D004164:Diphosphonates; D000939:Epitopes; D007093:Imidazoles; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D000077211:Zoledronic Acid