TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis.
Intestinal epithelial cells (IECs) produce thymic stromal lymphopoietin (TSLP); however, the in vivo influence of TSLP-TSLP receptor (TSLPR) interactions on immunity and inflammation in the intestine remains unclear. We show that TSLP-TSLPR interactions are critical for immunity to the intestinal pathogen Trichuris. Monoclonal antibody-mediated neutralization of TSLP or deletion of the TSLPR in normally resistant mice resulted in defective expression of Th2 cytokines and persistent infection. Susceptibility was accompanied by elevated expression of interleukin (IL) 12/23p40, interferon (IFN) gamma, and IL-17A, and development of severe intestinal inflammation. Critically, neutralization of IFN-gamma in Trichuris-infected TSLPR(-/-) mice restored Th2 cytokine responses and resulted in worm expulsion, providing the first demonstration of TSLPR-independent pathways for Th2 cytokine production. Additionally, TSLPR(-/-) mice displayed elevated production of IL-12/23p40 and IFN-gamma, and developed heightened intestinal inflammation upon exposure to dextran sodium sulfate, demonstrating a previously unrecognized immunoregulatory role for TSLP in a mouse model of inflammatory bowel disease.
Taylor
Betsy C
BC
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Zaph
Colby
C
Troy
Amy E
AE
Du
Yurong
Y
Guild
Katherine J
KJ
Comeau
Michael R
MR
Artis
David
D
D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000378:metabolism; D007109:Immunity / Q000276:immunology*; D007136:Immunoglobulins; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40; D007422:Intestines / Q000276:immunology / Q000469:parasitology* / Q000473:pathology*; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D009500:Neutralization Tests; D018121:Receptors, Cytokine / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014257:Trichuriasis / Q000276:immunology* / Q000469:parasitology; D014258:Trichuris / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D007136:Immunoglobulins; D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D018121:Receptors, Cytokine; C410591:Tslpr protein, mouse; D018664:Interleukin-12; D016264:Dextran Sulfate; D000094632:Thymic Stromal Lymphopoietin