Gamma delta T cells in the pathobiology of murine acute graft-versus-host disease. Evidence that gamma delta T cells mediate natural killer-like cytotoxicity in the host and that elimination of these cells from donors significantly reduces mortality.
NK-like cytotoxicity in F1-hybrid mice with acute GVH disease is mediated by donor-derived CD3+/CD4-/CD8- cells that can lyse both NK-sensitive YAC-1 target cells as well as NK-resistant targets such as BW1100 and P815. Our objective was to determine whether this activity is mediated by gamma delta TCR+ cells. We showed that NK-like cytotoxic activity in the spleen and lymph nodes of mice with acute GVH disease could be depleted by indirect complement-mediated lysis using an Ab against gamma delta TCR. When purified NK1.1+ spleen cells that had been positively selected on a magnetic cell separator were used as effector cells, we found that NK-like cytotoxicity was mediated only by gamma delta TCR+ cells, suggesting that cells with NK-like activity are gamma delta TCR+/NK1.1+. We showed by flow cytometry experiments that coexpression of NK1.1 and TCR-gamma delta occurred on a large proportion of large granular lymphocytes in the spleens of GVH mice, but was not detectable in normal control mice. In GVH mice, fewer than 10% of small agranular NK1.1+ lymphocytes coexpressed NK1.1+ and gamma delta TCR+. On the basis of this hypothesis, we postulate that graft-derived large granular lymphocytes develop the NK1.1+/gamma delta TCR+ phenotype during the reaction, and that these cells play a role in the pathogenesis of acute GVH disease. We performed experiments to determine whether depletion of gamma delta T cells from donor mice affected the outcome of lethal GVH disease and found that there was a significant reduction in mortality.
Ellison
C A
CA
Department of Immunology, University of Manitoba, Winnipeg, Canada.
MacDonald
G C
GC
Rector
E S
ES
Gartner
J G
JG
D000208:Acute Disease; D000818:Animals; D000941:Antigens / Q000276:immunology; D000950:Antigens, Ly; D000954:Antigens, Surface; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D015431:Weight Loss / Q000276:immunology
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta