title: Peptide library-based evaluation of T-cell receptor breadth detects defects in global and regulatory activation in human immunologic diseases.
abstract: The ability of T-cells to respond to foreign antigens and to appropriately regulate this response is crucial for maintaining immune homeostasis. Using combinatorial peptide libraries, we functionally measured broad T-cell reactivity and observed impaired reactivity in established models of T-cell receptor repertoire restriction and in previously unrecognized disease contexts. By concurrently analyzing T-regulatory and T-effector cells, we show strong functional correlation between these subsets in healthy individuals and, strikingly, that alterations of this balance are associated with T helper type 2 (Th2)-mediated disease in a lymphopenic setting. Finally, we demonstrate that peptide-based priming of polyclonal naive cells with relatively low concentrations skews toward Th2 differentiation. These findings provide unique insight into the pathophysiology and functional consequences of abnormal T-cell repertoires and into differentiation of human naive T-cells.
authors: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: John S
authors: JS
authors: Barber
authors: Lauren K
authors: LK
authors: Yokomizo
authors: Virginia
authors: V
authors: Sheikh
authors: Alexandra F
authors: AF
authors: Freeman
authors: Elizabeth
authors: E
authors: Garabedian
authors: Evert
authors: E
authors: van Dijk
authors: Robert
authors: R
authors: Sokolic
authors: Fabio
authors: F
authors: Candotti
authors: Nan-ping
authors: NP
authors: Weng
authors: Irini
authors: I
authors: Sereti
authors: Joshua D
authors: JD
authors: Milner
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002469:Cell Separation; D018920:Coculture Techniques; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D006801:Humans; D007154:Immune System Diseases / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008213:Lymphocyte Activation; D015233:Models, Statistical; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D018950:Lipopolysaccharide Receptors; D019151:Peptide Library; D010455:Peptides; D011948:Receptors, Antigen, T-Cell
keywords: atopy; immune deficiency
references: J Infect Dis. 2001 Apr 15;183(8):1285-9
references: 11262214
references: Nat Immunol. 2006 Apr;7(4):401-10
references: 16532000
references: Immunol Today. 1998 Sep;19(9):395-404
references: 9745202
references: Immunity. 2009 Dec 18;31(6):909-20
references: 20005134
references: Eur J Immunol. 2002 Aug;32(8):2292-9
references: 12209642
references: J Allergy Clin Immunol. 2004 Apr;113(4):734-41
references: 15100681
references: J Allergy Clin Immunol. 2005 Nov;116(5):1106-15
references: 16275384
references: Br J Haematol. 2000 Aug;110(2):434-7
references: 10971404
references: Immunity. 2006 Aug;25(2):249-59
references: 16879995
references: J Immunol. 2012 Mar 15;188(6):2537-44
references: 22327072
references: Science. 1996 Oct 4;274(5284):94-6
references: 8810254
references: J Biol Chem. 2012 Jan 6;287(2):1168-77
references: 22102287
references: Nat Genet. 2001 Jan;27(1):20-1
references: 11137993
references: J Immunol. 2011 Apr 1;186(7):4285-94
references: 21383244
references: J Immunol. 2001 Aug 15;167(4):2130-41
references: 11489997
references: J Exp Med. 2009 Jul 6;206(7):1525-34
references: 19564353
references: Blood. 2013 Feb 14;121(7):1112-23
references: 23255554
references: Immunity. 2007 Aug;27(2):203-13
references: 17707129
references: Structure. 1994 Apr 15;2(4):245-51
references: 8087551
references: Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):576-81
references: 17202252
references: Nat Rev Immunol. 2008 Mar;8(3):231-8
references: 18301425
references: Ciba Found Symp. 1997;204:94-100; discussion 100-4
references: 9107414
references: J Exp Med. 2008 Mar 17;205(3):711-23
references: 18332179
references: Nat Immunol. 2001 Nov;2(11):1067-76
references: 11668342
references: Nature. 1991 Oct 17;353(6345):622-7
references: 1656276
references: J Immunol. 2005 Jun 1;174(11):7446-52
references: 15905594
references: J Immunol. 2001 Jan 15;166(2):908-17
references: 11145667
references: Nat Med. 1999 Dec;5(12):1375-82
references: 10581079
references: J Immunol. 2012 Oct 1;189(7):3566-74
references: 22933635
references: Science. 1999 Oct 29;286(5441):958-61
references: 10542151
references: Blood. 2008 Jul 15;112(2):287-94
references: 18456875
references: J Immunol. 2010 Jun 15;184(12):6569-73
references: 20495070
references: Nat Immunol. 2012 Nov;13(11):1037-44
references: 23080204
references: J Exp Med. 2003 Sep 15;198(6):889-901
references: 12975455
references: Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15434-9
references: 15492218
references: Nature. 2002 Dec 5;420(6915):502-7
references: 12466842
references: Nat Rev Immunol. 2005 Nov;5(11):880-92
references: 16261175
references: J Immunol. 2012 May 1;188(9):4171-80
references: 22450809
references: Immunity. 2011 Nov 23;35(5):806-18
references: 22118528
references: J Immunol. 2010 Oct 1;185(7):3895-904
references: 20810983
references: Annu Rev Immunol. 2004;22:745-63
references: 15032595
references: Immunity. 2007 Sep;27(3):493-504
references: 17869133
references: J Immunol. 2012 May 1;188(9):4278-88
references: 22474020