Activated Human γδ T Cells as Stimulators of Specific CD8+ T-cell Responses to Subdominant Epstein Barr Virus Epitopes Potential for Immunotherapy of Cancer

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, gamma delta T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human 76 T cells to induce expansion of virus-specific T cells to Epstein Barr vu-LIS (EBV) antigens. Aminobisphosphonate-stimulated human peripheral blood-derived gamma delta T cells (V gamma 2+V delta 2+) acquired a dual phenotype characteristic for both APCs and effector memory T cells. Coincubation of activated gamma delta 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 CD3(+) CD8(+) cytolytic effector memory T cells. Furthermore, gamma delta T APCs efficiently processed and presented endogenous antigen, as demonstrated by the capacity of LMP2a gene-transduced 16 T cells to induce expansion of T cells with broad specificity for various LMP2a peptides. The capacity of autologous gamma delta T cells to induce LMP2a-specific autologous cytotoxic T lymphocytes was confirmed in 2 patients with Hodgkin lymphoma. In summary, bisphosphonate-activated human gamma delta 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.