The diabetogenic mouse MHC class II molecule I-Ag7 is endowed with a switch that modulates TCR affinity.
Genetic susceptibility to autoimmunity is frequently associated with specific MHC alleles. Diabetogenic MHC class II molecules, such as human HLA-DQ8 and mouse I-Ag7, typically have a small, uncharged amino acid residue at position 57 of their beta chain (beta57); this results in the absence of a salt bridge between beta57 and Argalpha76, which is adjacent to the P9 pocket of the peptide-binding groove. However, the influence of Argalpha76 on the selection of the TCR repertoire remains unknown, particularly when the MHC molecule binds a peptide with a neutral amino acid residue at position P9. Here, we have shown that diabetogenic MHC class II molecules bound to a peptide with a neutral P9 residue primarily selected and expanded cells expressing TCRs bearing a negatively charged residue in the first segment of their complementarity determining region 3beta. The crystal structure of one such TCR in complex with I-Ag7 bound to a peptide containing a neutral P9 residue revealed that a network of favorable long-range (greater than 4 A) electrostatic interactions existed among Argalpha76, the neutral P9 residue, and TCR, which supported the substantially increased TCR/peptide-MHC affinity. This network could be modulated or switched to a lower affinity interaction by the introduction of a negative charge at position P9 of the peptide. Our results support the existence of a switch at residue beta57 of the I-Ag7 and HLA-DQ8 class II molecules and potentially link normal thymic TCR selection with abnormal peripheral behavior.
Yoshida
Kenji
K
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
Corper
Adam L
AL
Herro
Rana
R
Jabri
Bana
B
Wilson
Ian A
IA
Teyton
Luc
L
D000818:Animals; D002469:Cell Separation; D018360:Crystallography, X-Ray / Q000379:methods; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D019281:Dimerization; D005260:Female; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000502:physiology; D006801:Humans; D006825:Hybridomas / Q000473:pathology; D007700:Kinetics; D051379:Mice; D008968:Molecular Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D011948:Receptors, Antigen, T-Cell
Biotechnology (N Y). 1993 Oct;11(10):1138-43
7764094
J Mol Biol. 2008 Apr 4;377(4):1104-16
18295796
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13838-43
9391114
Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
9757107
Int Immunol. 2002 Dec;14(12):1439-47
12456592
N Engl J Med. 1971 Jul 22;285(4):193-6
5087722
J Mol Graph. 1990 Mar;8(1):52-6, 29
2268628
Science. 1999 Dec 3;286(5446):1913-21
10583947
Nature. 1987 Oct 15-21;329(6140):599-604
3309680
EMBO J. 2000 Nov 1;19(21):5611-24
11060013
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
15572765
Acta Crystallogr D Biol Crystallogr. 2002 Nov;58(Pt 11):1948-54
12393927
Eur J Immunol. 2000 Sep;30(9):2497-506
11009082
Nature. 2000 Aug 17;406(6797):739-42
10963600
Nature. 2008 Nov 27;456(7221):534-8
19037317
Immunity. 2000 Jun;12(6):699-710
10894169
Nat Struct Biol. 2000 Jul;7(7):537-41
10876236
Diabetes. 1998 Oct;47(10):1570-7
9753294
Science. 2000 Apr 21;288(5465):505-11
10775108
J Mol Biol. 1972 Mar 14;64(2):497-509
5023185
Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9374-9
12082183
Biophys J. 1982 Oct;40(1):33-9
7139033
J Clin Invest. 2003 Sep;112(6):902-14
12975475
N Engl J Med. 1978 Apr 20;298(16):869-71
147420
J Immunol. 1998 Nov 1;161(9):4489-92
9794372
J Immunol. 2000 Sep 15;165(6):3214-25
10975837
Immunity. 1996 Feb;4(2):189-94
8624809
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
19461840
J Clin Invest. 2005 Aug;115(8):2268-76
16075062
Nat Genet. 2007 Jul;39(7):857-64
17554260
Nat Struct Biol. 1996 May;3(5):427-31
8612072