title: Innate recognition of cell wall β-glucans drives invariant natural killer T cell responses against fungi.
abstract: iNKT cells are innate T lymphocytes recognizing endogenous and foreign lipid antigens presented in the MHC-like molecule CD1d. The semi-invariant iNKT cell TCR can detect certain bacterial and parasitic lipids and drive iNKT cell responses. How iNKT cells respond to fungi, however, is unknown. We found that CD1d-deficient mice, which lack iNKT cells, poorly control infection with the fungal pathogen Aspergillus fumigatus. Furthermore, A. fumigatus rapidly activates iNKT cells in vivo and in vitro in the presence of APCs. Surprisingly, despite a requirement for CD1d recognition, the antifungal iNKT cell response does not require fungal lipids. Instead, Dectin-1- and MyD88-mediated responses to β-1,3 glucans, major fungal cell-wall polysaccharides, trigger IL-12 production by APCs that drives self-reactive iNKT cells to secrete IFN-γ. Innate recognition of β-1,3 glucans also drives iNKT cell responses against Candida, Histoplasma, and Alternaria, suggesting that this mechanism may broadly define the basis for antifungal iNKT cell responses.
authors.affiliation: Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. nadia_cohen@hms.harvard.edu
authors.forename: Nadia R
authors.initials: NR
authors.lastname: Cohen
authors.forename: Raju V V
authors.initials: RV
authors.lastname: Tatituri
authors.forename: Amariliz
authors.initials: A
authors.lastname: Rivera
authors.forename: Gerald F M
authors.initials: GF
authors.lastname: Watts
authors.forename: Edy Y
authors.initials: EY
authors.lastname: Kim
authors.forename: Asako
authors.initials: A
authors.lastname: Chiba
authors.forename: Beth B
authors.initials: BB
authors.lastname: Fuchs
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Mylonakis
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Levitz
authors.forename: Manfred
authors.initials: M
authors.lastname: Brigl
authors.forename: Michael B
authors.initials: MB
authors.lastname: Brenner
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D055610:Antigens, CD1d / Q000276:immunology; D001228:Aspergillosis / Q000276:immunology* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology*; D002473:Cell Wall / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000382:microbiology*; D047071:beta-Glucans / Q000276:immunology*
chemical_list: D055610:Antigens, CD1d; D047071:beta-Glucans
references.citation: Am J Respir Crit Care Med. 2008 Oct 1;178(7):745-56
references.pmid: 18596223
references.citation: Nat Immunol. 2007 Jan;8(1):39-46
references.pmid: 17159982
references.citation: J Immunol. 2007 Mar 1;178(5):2706-13
references.pmid: 17312112
references.citation: Med Mycol. 2001;39 Suppl 1:9-17
references.pmid: 11800273
references.citation: J Clin Invest. 1982 Mar;69(3):617-31
references.pmid: 7037853
references.citation: Nat Immunol. 2007 Jan;8(1):31-8
references.pmid: 17159984
references.citation: Nat Immunol. 2010 Mar;11(3):197-206
references.pmid: 20139988
references.citation: J Immunol. 2009 Feb 15;182(4):1846-53
references.pmid: 19201836
references.citation: Blood. 2010 Dec 9;116(24):5394-402
references.pmid: 20807886
references.citation: Nat Immunol. 2009 Jul;10(7):669-71
references.pmid: 19536187
references.citation: J Biol Chem. 2007 Feb 16;282(7):4561-4572
references.pmid: 17179146
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20490-5
references.pmid: 18077358
references.citation: Immunology. 2003 Dec;110(4):519-26
references.pmid: 14632651
references.citation: Nat Immunol. 2006 Sep;7(9):978-86
references.pmid: 16921381
references.citation: Eur J Immunol. 2009 May;39(5):1379-86
references.pmid: 19291703
references.citation: J Agric Food Chem. 2004 Dec 29;52(26):7905-10
references.pmid: 15612774
references.citation: Eur J Immunol. 2008 Jul;38(7):1913-22
references.pmid: 18521958
references.citation: Annu Rev Immunol. 2007;25:297-336
references.pmid: 17150027
references.citation: Curr Opin Microbiol. 2010 Aug;13(4):409-15
references.pmid: 20627805
references.citation: Carbohydr Res. 2004 Sep 13;339(13):2255-65
references.pmid: 15337454
references.citation: J Biochem. 1975 Oct;78(4):817-20
references.pmid: 175047
references.citation: Nat Med. 2008 Jun;14(6):633-40
references.pmid: 18488036
references.citation: Immunology. 2009 Nov;128(3):324-33
references.pmid: 20067532
references.citation: Infect Immun. 2011 May;79(5):1961-70
references.pmid: 21357722
references.citation: Semin Immunol. 2010 Apr;22(2):79-86
references.pmid: 19948416
references.citation: Adv Immunol. 2009;102:1-94
references.pmid: 19477319
references.citation: Nat Immunol. 2002 Dec;3(12):1163-8
references.pmid: 12415264
references.citation: J Immunol. 2009 Apr 15;182(8):4938-46
references.pmid: 19342673
references.citation: Infect Immun. 2009 May;77(5):1774-81
references.pmid: 19273561
references.citation: Infect Immun. 2001 Jan;69(1):213-20
references.pmid: 11119508
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10685-90
references.pmid: 15243159
references.citation: J Clin Invest. 2008 Dec;118(12):4036-48
references.pmid: 19033672
references.citation: Mol Microbiol. 2007 Oct;66(2):279-90
references.pmid: 17854405
references.citation: Nature. 2005 Mar 24;434(7032):525-9
references.pmid: 15791258
references.citation: J Virol. 2002 May;76(9):4294-303
references.pmid: 11932395
references.citation: Cell Microbiol. 2007 Feb;9(2):368-81
references.pmid: 16953804
references.citation: Curr Opin Immunol. 2009 Feb;21(1):30-7
references.pmid: 19223162
references.citation: Am J Respir Crit Care Med. 2010 Sep 15;182(6):841-7
references.pmid: 20508216
references.citation: Nature. 2005 Mar 24;434(7032):520-5
references.pmid: 15791257
references.citation: Nat Immunol. 2003 Dec;4(12):1230-7
references.pmid: 14578883
references.citation: Med Mycol. 2005 May;43 Suppl 1:S15-22
references.pmid: 16110787
references.citation: Cell Microbiol. 2011 Feb;13(2):177-85
references.pmid: 21091925
references.citation: PLoS Pathog. 2008 Dec;4(12):e1000239
references.pmid: 19079582
references.citation: J Exp Med. 1999 Apr 5;189(7):1121-8
references.pmid: 10190903
references.citation: Immunol Rev. 2009 Jul;230(1):38-50
references.pmid: 19594628
references.citation: Nat Med. 2002 Jun;8(6):588-93
references.pmid: 12042809
references.citation: Immunity. 2007 Oct;27(4):597-609
references.pmid: 17950005
references.citation: Lipids. 1976 Dec;11(12):837-44
references.pmid: 1011938
references.citation: Eur J Immunol. 2005 Jun;35(6):1692-701
references.pmid: 15915536
references.citation: Curr Top Med Mycol. 1993;5:1-26
references.pmid: 8242797
references.citation: Microbes Infect. 2009 Oct;11(12):919-27
references.pmid: 19615460
references.citation: Curr Opin Immunol. 2009 Aug;21(4):391-6
references.pmid: 19646850
references.citation: J Exp Med. 2011 Jun 6;208(6):1163-77
references.pmid: 21555485
references.citation: Immunity. 2010 Aug 27;33(2):216-28
references.pmid: 20727792
references.citation: J Immunol. 2008 Sep 15;181(6):4279-86
references.pmid: 18768886
references.citation: Infect Immun. 2008 Mar;76(3):952-8
references.pmid: 18039832
references.citation: Infect Immun. 1998 Oct;66(10):4994-5000
references.pmid: 9746609
references.citation: Microbes Infect. 2011 Feb;13(2):151-9
references.pmid: 20971208
references.citation: Cell Microbiol. 2010 Jul;12(7):863-72
references.pmid: 20482553
references.citation: Eur J Immunol. 2008 Feb;38(2):500-6
references.pmid: 18200499
references.citation: Infect Immun. 2001 Nov;69(11):6643-50
references.pmid: 11598033
references.citation: FEMS Yeast Res. 2006 Jun;6(4):469-79
references.pmid: 16696643
references.citation: J Exp Med. 2004 Oct 4;200(7):895-904
references.pmid: 15466622
references.citation: Nat Rev Microbiol. 2007 Jun;5(6):405-17
references.pmid: 17487145
references.citation: J Immunol. 2001 Dec 1;167(11):6525-32
references.pmid: 11714821