Structural alterations in peptide-MHC recognition by self-reactive T cell receptors.
The crystal structures of five autoimmune T cell receptor (TCR)-peptide-MHC complexes reveal substantial structural alterations compared to antimicrobial TCRs. The two human TCRs bind their self-peptide-MHC ligands with an altered topology, while the three mouse receptors recognize a self-peptide that only partially fills the MHC-binding groove. In most cases the peptide is contacted only by a subset of available TCR complementarity-determining loops and there is a paucity of hydrogen bonds from TCR to peptide. These suboptimal binding properties may have enabled escape from negative thymic selection. While only minute amounts of antigen are typically available for negative selection, the antigens recognized by many autoimmune TCRs are abundant in the target organ. Such compensatory mechanisms can allow self-reactive T cells with altered TCR-binding properties to be pathogenic.
Wucherpfennig
Kai W
KW
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. kai_wucherpfennig@dfci.harvard.edu
Call
Melissa J
MJ
Deng
Lu
L
Mariuzza
Roy
R
D000818:Animals; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D015551:Autoimmunity; D006649:Histocompatibility Antigens / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000737:chemistry* / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology*
D001324:Autoantigens; D006649:Histocompatibility Antigens; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell
Immunity. 2009 Mar 20;30(3):348-57
19303388
Nat Immunol. 2007 Sep;8(9):975-83
17694060
Immunity. 2008 Mar;28(3):324-34
18308592
EMBO J. 2005 Sep 7;24(17):2968-79
16079912
Nat Immunol. 2006 Mar;7(3):256-64
16474394
J Immunol. 1999 Jan 1;162(1):338-44
9886404
J Exp Med. 2008 Apr 14;205(4):967-79
18391064
J Exp Med. 1994 Jan 1;179(1):279-90
7505801
Springer Semin Immunopathol. 2003 Aug;25(1):3-18
12904888
Nature. 2005 May 12;435(7039):220-3
15889095
EMBO J. 2000 Nov 1;19(21):5611-24
11060013
Immunity. 2002 Jul;17(1):83-94
12150894
J Exp Med. 2003 Dec 1;198(11):1627-9
14657216
Eur J Immunol. 2000 Sep;30(9):2497-506
11009082
Science. 2002 Nov 15;298(5597):1395-401
12376594
Immunity. 2005 Jan;22(1):81-92
15664161
Nat Immunol. 2005 May;6(5):490-6
15821740
Nat Genet. 1999 Nov;23(3):343-7
10610182
Science. 1999 Dec 3;286(5446):1913-21
10583947
Immunity. 2009 Feb 20;30(2):193-203
19167249
Annu Rev Immunol. 2008;26:171-203
18304006
Annu Rev Immunol. 1990;8:579-621
2188675
J Immunol. 1999 Dec 15;163(12):6424-34
10586032
Nature. 1986 Nov 20-26;324(6094):258-60
2431317
J Immunol. 2000 Sep 15;165(6):3214-25
10975837
Nat Med. 1998 Jun;4(6):713-7
9623982
Annu Rev Immunol. 2006;24:419-66
16551255
J Biol Chem. 2000 Jan 7;275(1):312-21
10617620
Science. 1996 Oct 11;274(5285):209-19
8824178
Immunity. 1998 May;8(5):571-80
9620678
Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15523-8
18824684
Nat Immunol. 2007 Apr;8(4):398-408
17334368
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6818-23
11391002