title: Structural basis for enabling T-cell receptor diversity within biased virus-specific CD8+ T-cell responses.
abstract: Pathogen-specific responses are characterized by preferred profiles of peptide+class I MHC (pMHCI) glycoprotein-specific T-cell receptor (TCR) Variable (V)-region use. How TCRV-region bias impacts TCRαβ heterodimer selection and resultant diversity is unclear. The D(b)PA(224)-specific TCR repertoire in influenza A virus-infected C57BL/6J (B6) mice exhibits a preferred TCRV-region bias toward the TRBV29 gene segment and an optimal complementarity determining region (CDR3) β-length of 6 aa. Despite these restrictions, D(b)PA(224)-specific BV29(+) T cells use a wide array of unique CDR3β sequences. Structural characterization of a single, TRBV29(+)D(b)P(A224)-specific TCRαβ-pMHCI complex demonstrated that CDR3α amino acid side chains made specific peptide interactions, but the CDR3β main chain exclusively contacted peptides. Thus, length but not amino acid sequence was key for recognition and flexibility in Vβ-region use. In support of this hypothesis, retrovirus expression of the D(b)PA(224)-specific TCRVα-chain was used to constrain pairing within a naive/immune epitope-specific repertoire. The retrogenic TCRVα paired with a diversity of CDR3βs in the context of a preferred TCRVβ spectrum. Overall, these data provide an explanation for the combination of TCRV region bias and diversity within selected repertoires, even as they maintain exquisite pMHCI specificity.
authors: Department of Microbiology and Immunology, Bio21, Department of Biochemistry, University of Melbourne, Parkville, VIC 3010, Australia.
authors: E Bridie
authors: EB
authors: Day
authors: Carole
authors: C
authors: Guillonneau
authors: Stephanie
authors: S
authors: Gras
authors: Nicole L
authors: NL
authors: La Gruta
authors: Dario A A
authors: DA
authors: Vignali
authors: Peter C
authors: PC
authors: Doherty
authors: Anthony W
authors: AW
authors: Purcell
authors: Jamie
authors: J
authors: Rossjohn
authors: Stephen J
authors: SJ
authors: Turner
references: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4942-7
references: 15037737
references: PLoS Pathog. 2010 Nov 18;6(11):e1001198
references: 21124993
references: J Exp Med. 1994 Sep 1;180(3):861-72
references: 8064237
references: Immunity. 2008 Feb;28(2):171-82
references: 18275829
references: Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10608-13
references: 20483993
references: Nat Immunol. 2003 Jul;4(7):657-63
references: 12796775
references: J Exp Med. 1995 Jan 1;181(1):79-91
references: 7807026
references: Immunity. 2009 Feb 20;30(2):193-203
references: 19167249
references: Nat Rev Immunol. 2006 Dec;6(12):883-94
references: 17110956
references: J Exp Med. 2005 Feb 21;201(4):523-33
references: 15710651
references: Nucleic Acids Res. 2001 Jan 1;29(1):207-9
references: 11125093
references: J Mol Biol. 2007 Sep 14;372(2):535-48
references: 17658550
references: Nat Immunol. 2009 Feb;10(2):143-7
references: 19148199
references: Nat Biotechnol. 2004 May;22(5):589-94
references: 15064769
references: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19414-9
references: 20974936
references: Nat Immunol. 2007 Mar;8(3):268-76
references: 17259989
references: Nat Immunol. 2007 Sep;8(9):975-83
references: 17694060
references: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18691-6
references: 17130450
references: J Immunol. 2004 May 1;172(9):5553-60
references: 15100298
references: J Clin Invest. 2007 Aug;117(8):2176-85
references: 17627303
references: Nat Immunol. 2005 Nov;6(11):1114-22
references: 16186824
references: J Exp Med. 1994 Dec 1;180(6):2335-40
references: 7964506
references: Science. 2002 Nov 29;298(5599):1797-800
references: 12459592
references: J Exp Med. 2009 Apr 13;206(4):923-36
references: 19349463
references: J Exp Med. 2002 Apr 15;195(8):991-1001
references: 11956290
references: Nature. 2009 Apr 23;458(7241):1043-6
references: 19262510
references: J Biol Chem. 2009 Oct 2;284(40):27281-9
references: 19605354
references: Immunity. 2004 Nov;21(5):669-79
references: 15539153
references: Immunity. 2004 Dec;21(6):793-803
references: 15589168
references: Immunity. 2003 Apr;18(4):549-59
references: 12705857
references: J Immunol. 2009 Jul 1;183(1):430-7
references: 19542454
references: Nat Protoc. 2006;1(1):406-17
references: 17406263
references: J Exp Med. 2001 Nov 5;194(9):1385-90
references: 11696602
references: Nat Immunol. 2005 Apr;6(4):382-9
references: 15735650
references: Proc Natl Acad Sci U S A. 1993 May 1;90(9):4319-23
references: 8483950
references: J Exp Med. 2003 Aug 4;198(3):399-410
references: 12885871
references: Annu Rev Immunol. 2006;24:419-66
references: 16551255
references: J Clin Invest. 2010 Jun;120(6):1885-94
references: 20440073
references: Immunity. 2003 Jan;18(1):53-64
references: 12530975
references: Eur J Immunol. 2010 Sep;40(9):2470-81
references: 20690181