title: Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It.
abstract: MHC alloantigen is recognized by two pathways: "directly," intact on donor cells, or "indirectly," as self-restricted allopeptide. The duration of each pathway, and its relative contribution to allograft vasculopathy, remain unclear. Using a murine model of chronic allograft rejection, we report that direct-pathway CD4 T cell alloresponses, as well as indirect-pathway responses against MHC class II alloantigen, are curtailed by rapid elimination of donor hematopoietic antigen-presenting cells. In contrast, persistent presentation of epitope resulted in continual division and less-profound contraction of the class I allopeptide-specific CD4 T cell population, with approximately 10,000-fold more cells persisting than following acute allograft rejection. This expanded population nevertheless displayed sub-optimal anamnestic responses and was unable to provide co-stimulation-independent help for generating alloantibody. Indirect-pathway CD4 T cell responses are heterogeneous. Appreciation that responses against particular alloantigens dominate at late time points will likely inform development of strategies aimed at improving transplant outcomes.
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Ali
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Negus
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Conlon
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors.forename: Ines G
authors.initials: IG
authors.lastname: Harper
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Qureshi
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors.forename: Reza
authors.initials: R
authors.lastname: Motallebzadeh
authors.affiliation: NIH Tetramer Facility, Emory/Yerkes, 954 Gatewood Road, Atlanta, GA 30329, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Willis
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Saeb-Parsy
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Bolton
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.affiliation: University of Cambridge, School of Clinical Medicine, Cambridge CB2 0QQ, UK. Electronic address: gjp25@cam.ac.uk.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Pettigrew
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007113:Immunity, Innate; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D015395:Histocompatibility Antigens Class I; D007519:Isoantigens; D010455:Peptides