title: CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection.
abstract: Adaptive CD8 T-cell immunity is the principal arm of the cellular alloimmune response, but its development requires help. This can be provided by CD4 T cells that recognize alloantigen "indirectly," as self-restricted allopeptide, but this process remains unexplained, because the target epitopes for CD4 and CD8 T-cell recognition are "unlinked" on different cells (recipient and donor antigen presenting cells (APCs), respectively). Here, we test the hypothesis that the presentation of intact and processed MHC class I alloantigen by recipient dendritic cells (DCs) (the "semidirect" pathway) allows linked help to be delivered by indirect-pathway CD4 T cells for generating destructive cytotoxic CD8 T-cell alloresponses. We show that CD8 T-cell-mediated rejection of murine heart allografts that lack hematopoietic APCs requires host secondary lymphoid tissue (SLT). SLT is necessary because within it, recipient dendritic cells can acquire MHC from graft parenchymal cells and simultaneously present it as intact protein to alloreactive CD8 T cells and as processed peptide alloantigen for recognition by indirect-pathway CD4 T cells. This enables delivery of essential help for generating cytotoxic CD8 T-cell responses that cause rapid allograft rejection. In demonstrating the functional relevance of the semidirect pathway to transplant rejection, our findings provide a solution to a long-standing conundrum as to why SLT is required for CD8 T-cell allorecognition of graft parenchymal cells and suggest a mechanism by which indirect-pathway CD4 T cells provide help for generating effector cytotoxic CD8 T-cell alloresponses at late time points after transplantation.
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Harper
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom ja297@cam.ac.uk gjp25@cam.ac.uk.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Ali
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wlodek
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Marg C
authors.initials: MC
authors.lastname: Negus
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Ines G
authors.initials: IG
authors.lastname: Harper
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Manu
authors.initials: M
authors.lastname: Chhabra
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Qureshi
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Mekhola
authors.initials: M
authors.lastname: Mallik
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Bolton
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.affiliation: School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom ja297@cam.ac.uk gjp25@cam.ac.uk.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Pettigrew
mesh_terms: D064591:Allografts; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout
chemical_list: D015395:Histocompatibility Antigens Class I; D007519:Isoantigens
keywords: CD8 cytotoxicity; alloimmunity; allorecognition; semidirect allorecognition; semidirect pathway