Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis.
Intestinal epithelial cells (IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal (GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown. Here we show that IEC-intrinsic IkappaB kinase (IKK)-beta-dependent gene expression is a critical regulator of responses of dendritic cells and CD4+ T cells in the GI tract. Mice with an IEC-specific deletion of IKK-beta show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4+ T helper type 2 (T(H)2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-alpha, increased levels of CD4+ T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta in IECs to promote CD4+ T(H)2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK-beta-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.
Zaph
Colby
C
Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Troy
Amy E
AE
Taylor
Betsy C
BC
Berman-Booty
Lisa D
LD
Guild
Katherine J
KJ
Du
Yurong
Y
Yost
Evan A
EA
Gruber
Achim D
AD
May
Michael J
MJ
Greten
Florian R
FR
Eckmann
Lars
L
Karin
Michael
M
Artis
David
D
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000172:deficiency / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004847:Epithelial Cells / Q000201:enzymology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D018928:Immunity, Mucosal / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007422:Intestines / Q000166:cytology / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D014258:Trichuris / Q000276:immunology / Q000502:physiology; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D020381:Interleukin-17; D016328:NF-kappa B; D007371:Interferon-gamma; D051550:I-kappa B Kinase; D000094632:Thymic Stromal Lymphopoietin