Critical role of host γδ T cells in experimental acute graft-versus-host disease

gamma delta T cells localize to target tissues of graft-versus-host disease (GVHD) and therefore we investigated the role of host gamma delta T cells in the pathogenesis of acute GVHD in several well-characterized allogeneic bone marrow transplantation (BMT) models. Depletion of host gamma delta T cells in wild-type (wt) B6 recipients by administration of anti-T-cell receptor (TCR) gamma delta monoclonal antibody reduced GVHD, and gamma delta T-cell-deficient (gamma delta(-/-)) BM transplant recipients experienced markedly improved survival compared with normal controls (63% vs 10%, P <.001). gamma delta T cells were responsible for this difference because reconstitution of gamma delta(-/-) recipients with gamma delta T cells restored GVHD mortality. gamma delta(-/-) recipients showed decreased serum levels of tumor necrosis factor alpha (TNF-alpha), less GVHD histopathologic damage, and reduced donor T-cell expansion. Mechanistic analysis of this phenomenon demonstrated that dendritic cells (DCs) from gamma delta(-/-) recipients exhibited less allostimulatory capacity compared to wt DCs after irradiation. Normal DCs derived from BM caused greater allogeneic T-cell proliferation when cocultured with gamma delta T cells than DCs cocultured with medium alone. This enhancement did not depend on interferon,gamma (IFN-gamma), TNF-alpha, or CD40 ligand but did depend on cell-to-cell contact. These data demonstrated that the host gamma delta T cells exacerbate GVHD by enhancing the allostimulatory capacity of host antigen-presenting cells.