title: Copresentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T cells by indirect-pathway CD4 T cells.
abstract: In transplantation, direct-pathway CD8 T cells that recognize alloantigen on donor cells require CD4 help for activation and cytolytic function. The ability of indirect-pathway CD4 T cells to provide this help remains unexplained, because a fundamental requirement for epitope linkage is seemingly broken. The simultaneous presentation, by host dendritic cells (DCs), of both intact MHC class I alloantigen and processed alloantigen would deliver linked help, but has not been demonstrated definitively. In this study, we report that following in vitro coculture with BALB/c DCs, small numbers (~1.5%) of C57BL/6 (B6) DCs presented acquired H-2(d) alloantigen both as processed allopeptide and as unprocessed Ag. This represented class I alloantigen provides a conformational epitope for direct-pathway allorecognition, because B6 DCs isolated from cocultures and transferred to naive B6 mice provoked cytotoxic CD8 T cell alloimmunity. Crucially, this response was dependent upon simultaneous presentation of class II-restricted allopeptide, because despite acquiring similar amounts of H-2(d) alloantigen upon coculture, MHC class II-deficient B6 DCs failed to elicit cytotoxic alloimmunity. The relevance of this pathway to solid-organ transplantation was then confirmed by the demonstration that CD8 T cell cytotoxicity was provoked in secondary recipients by transfer of DCs purified from wild-type, but not from MHC class II-deficient, C57BL/6 recipients of BALB/c heart transplants. These experiments demonstrate that representation of conformationally intact MHC alloantigen by recipient APC can induce cytotoxic alloimmunity, but simultaneous copresentation of processed allopeptide is essential, presumably because this facilitates linked recognition by indirect-pathway CD4 Th cells.
authors: Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors: Siva
authors: S
authors: Sivaganesh
authors: Simon J
authors: SJ
authors: Harper
authors: Thomas M
authors: TM
authors: Conlon
authors: Chris J
authors: CJ
authors: Callaghan
authors: Kourosh
authors: K
authors: Saeb-Parsy
authors: Margaret C
authors: MC
authors: Negus
authors: Reza
authors: R
authors: Motallebzadeh
authors: Eleanor M
authors: EM
authors: Bolton
authors: J Andrew
authors: JA
authors: Bradley
authors: Gavin J
authors: GJ
authors: Pettigrew
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology*; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007519:Isoantigens / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice
chemical_list: D006649:Histocompatibility Antigens; D007519:Isoantigens; D008565:Membrane Proteins
references: J Exp Med. 1996 Feb 1;183(2):699-703
references: 8627185
references: Immunity. 2005 Nov;23(5):503-14
references: 16286018
references: Immunity. 1997 Aug;7(2):197-208
references: 9285405
references: J Immunol. 2006 Feb 15;176(4):2190-6
references: 16455975
references: Blood. 2012 Sep 6;120(10):2055-63
references: 22705596
references: Nature. 2001 May 24;411(6836):489-94
references: 11373683
references: J Immunol. 2008 Mar 1;180(5):3081-90
references: 18292531
references: J Exp Med. 2002 Jan 7;195(1):1-13
references: 11781360
references: Science. 2005 Mar 11;307(5715):1630-4
references: 15761154
references: J Thorac Cardiovasc Surg. 1969 Feb;57(2):225-9
references: 4884735
references: Nature. 1998 Jun 4;393(6684):478-80
references: 9624004
references: J Immunol. 2012 Dec 15;189(12):5694-702
references: 23150718
references: Front Biosci. 1999 May 15;4:D476-80
references: 10331992
references: Transplantation. 2006 Aug 27;82(4):582-91
references: 16958183
references: FEBS Lett. 2009 Jun 5;583(11):1792-9
references: 19289124
references: J Immunol. 2006 Jan 15;176(2):750-61
references: 16393958
references: J Immunol. 2012 Dec 15;189(12):5703-12
references: 23162131
references: Immunity. 2002 Aug;17(2):211-20
references: 12196292
references: J Immunol. 2000 May 1;164(9):4627-34
references: 10779766
references: Nature. 1989 Apr 27;338(6218):765-8
references: 2469959
references: Nat Med. 2000 Jun;6(6):686-8
references: 10835686
references: Curr Opin Immunol. 2004 Oct;16(5):550-7
references: 15341998
references: Nat Med. 2002 Mar;8(3):233-9
references: 11875493
references: FASEB J. 2008 Nov;22(11):3776-84
references: 18632850
references: Eur J Immunol. 2007 Mar;37(3):696-705
references: 17266175
references: J Immunol. 2012 Mar 15;188(6):2643-52
references: 22323543
references: J Exp Med. 1988 Jul 1;168(1):33-45
references: 2456372
references: J Exp Med. 2003 Oct 6;198(7):1089-102
references: 14517277
references: Nature. 1998 Jun 4;393(6684):474-8
references: 9624003
references: J Immunol. 2004 Oct 15;173(8):4828-37
references: 15470023
references: Science. 1999 Oct 29;286(5441):952-4
references: 10542149
references: Nat Immunol. 2003 Sep;4(9):815
references: 12942076
references: J Immunol. 2012 Nov 15;189(10):4728-39
references: 23066151
references: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10338-43
references: 10468609
references: Immunol Today. 1999 Feb;20(2):77-82
references: 10098326
references: Am J Transplant. 2011 Apr;11(4):826-31
references: 21401861
references: Nature. 1998 Jun 4;393(6684):480-3
references: 9624005
references: Transplantation. 2007 Apr 15;83(7):931-7
references: 17460565
references: J Exp Med. 1994 Mar 1;179(3):865-72
references: 8113680
references: Blood. 2000 Jun 1;95(11):3473-7
references: 10828031
references: FASEB J. 2012 Jan;26(1):51-62
references: 21926237