Critical role of host gammadelta T cells in experimental acute graft-versus-host disease.
Gammadelta T cells localize to target tissues of graft-versus-host disease (GVHD) and therefore we investigated the role of host gammadelta T cells in the pathogenesis of acute GVHD in several well-characterized allogeneic bone marrow transplantation (BMT) models. Depletion of host gammadelta T cells in wild-type (wt) B6 recipients by administration of anti-T-cell receptor (TCR) gammadelta monoclonal antibody reduced GVHD, and gammadelta T-cell-deficient (gammadelta-/-) BM transplant recipients experienced markedly improved survival compared with normal controls (63% vs 10%, P < .001). gammadelta T cells were responsible for this difference because reconstitution of gammadelta-/- recipients with gammadelta T cells restored GVHD mortality. gammadelta-/- 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 gammadelta-/- 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 gammadelta 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 gammadelta T cells exacerbate GVHD by enhancing the allostimulatory capacity of host antigen-presenting cells.
Maeda
Yoshinobu
Y
Department of Internal Medicine, 6310 CCGC, University of Michigan Cancer Center, 1500 East Medical Center Dr, Ann Arbor, MI 48109-0942, USA.
Reddy
Pavan
P
Lowler
Kathleen P
KP
Liu
Chen
C
Bishop
Dennis Keith
DK
Ferrara
James L M
JL
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology / Q000473:pathology; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics
D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007371:Interferon-gamma