title: Immune insufficiency during GVHD is due to defective antigen presentation within dendritic cell subsets.
abstract: Alloreactivity after transplantation is associated with profound immune suppression, and consequent opportunistic infection results in high morbidity and mortality. This immune suppression is most profound during GVHD after bone marrow transplantation where an inflammatory cytokine storm dominates. Contrary to current dogma, which avers that this is a T-cell defect, we demonstrate that the impairment lies within conventional dendritic cells (cDCs). Significantly, exogenous antigens can only be presented by the CD8(-) cDC subset after bone marrow transplantation, and inflammation during GVHD specifically renders the MHC class II presentation pathway in this population incompetent. In contrast, both classic and cross-presentation within MHC class I remain largely intact. Importantly, this defect in antigen processing can be partially reversed by TNF inhibition or the adoptive transfer of donor cDCs generated in the absence of inflammation.
authors.affiliation: Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, Brisbane, Australia. kate.markey@qimr.edu.au
authors.forename: Kate A
authors.initials: KA
authors.lastname: Markey
authors.forename: Motoko
authors.initials: M
authors.lastname: Koyama
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lineburg
authors.forename: Yana A
authors.initials: YA
authors.lastname: Wilson
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Olver
authors.forename: Neil C
authors.initials: NC
authors.lastname: Raffelt
authors.forename: Alistair L J
authors.initials: AL
authors.lastname: Don
authors.forename: Antiopi
authors.initials: A
authors.lastname: Varelias
authors.forename: Renee J
authors.initials: RJ
authors.lastname: Robb
authors.forename: Melody
authors.initials: M
authors.lastname: Cheong
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.forename: Javier
authors.initials: J
authors.lastname: Vega-Ramos
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.forename: Jose A
authors.initials: JA
authors.lastname: Villadangos
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; D007519:Isoantigens; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma