title: Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease.
abstract: Previous studies have shown a correlation between pretransplant conditioning intensity, intestinal barrier loss, and graft-versus-host disease (GVHD) severity. However, because irradiation and other forms of pretransplant conditioning have pleiotropic effects, the precise role of intestinal barrier loss in GVHD pathogenesis remains unclear. We developed GVHD models that allowed us to isolate the specific contributions of distinct pretransplant variables. Intestinal damage was required for the induction of minor mismatch [major histocompatibility complex (MHC)-matched] GVHD, but was not necessary for major mismatch GVHD, demonstrating fundamental pathogenic distinctions between these forms of disease. Moreover, recipient natural killer (NK) cells prevented minor mismatch GVHD by limiting expansion and target organ infiltration of alloreactive T cells via a perforin-dependent mechanism, revealing an immunoregulatory function of MHC-matched recipient NK cells in GVHD. Minor mismatch GVHD required MyD88-mediated Toll-like receptor 4 (TLR4) signaling on donor cells, and intestinal damage could be bypassed by parenteral lipopolysaccharide (LPS) administration, indicating a critical role for the influx of bacterial components triggered by intestinal barrier loss. In all, the data demonstrate that pretransplant conditioning plays a dual role in promoting minor mismatch GVHD by both depleting recipient NK cells and inducing intestinal barrier loss.
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sam C
authors.initials: SC
authors.lastname: Nalle
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: H Aimee
authors.initials: HA
authors.lastname: Kwak
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Edelblum
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Nora E
authors.initials: NE
authors.lastname: Joseph
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Gurminder
authors.initials: G
authors.lastname: Singh
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Galina F
authors.initials: GF
authors.lastname: Khramtsova
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Mortenson
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA. jturner@bsd.uchicago.edu psavage@bsd.uchicago.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Savage
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA. jturner@bsd.uchicago.edu psavage@bsd.uchicago.edu.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008070:Lipopolysaccharides; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; C499308:Rag2 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4