Regulation of helminth-induced Th2 responses by thymic stromal lymphopoietin.
Thymic stromal lymphopoietin was recently identified as a master switch for the development of allergen-driven Th2 responses. However, the role of thymic stromal lymphopoietin (TSLP) in the development of helminth-induced Th2 responses is unclear. Here, using TSLPR(-/-) mice, we show that while TSLPR signaling participates in the development of Schistosoma mansoni egg-induced CD4(+) Th2 responses, it plays only a transient role in the development of Th2-dependent pathology in the lung, liver, and intestine. Studies conducted in a pulmonary granuloma model showed that while a reduction in IL-4/IL-13-dependent granulomatous inflammation and tissue eosinophilia was observed in TSLPR(-/-) mice undergoing a primary response, lesion formation was not affected during a secondary granulomatous response, even though IL-5 and IL-13 were modestly reduced in the knockout mice. To evaluate the importance of TSLPR signaling in the development of a chronic Th2-dependent response, TSLPR(-/-) mice were also infected with S. mansoni cercariae. Here, the only significant difference noted in TSLPR(-/-) mice was a modest decrease in liver fibrosis in acutely infected animals. The transient decrease in fibrosis was associated with increased production of the antifibrotic cytokine IFN-gamma and decreased production of the profibrotic cytokine IL-13. Although the altered cytokine response persisted in chronically infected TSLPR(-/-) mice, it failed to reduce granuloma formation or fibrosis, confirming that TSLPR signaling plays a limited role in the development of chronic Th2-dependent pathology. Collectively, these findings suggest that while TSLPR signaling serves a key role in allergen-driven Th2 responses, it exerts minor regulatory activity during this chronic helminth infection.
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Thirumalai R
TR
Ramalingam
John T
JT
Pesce
Margaret M
MM
Mentink-Kane
Satish
S
Madala
Allen W
AW
Cheever
Michael R
MR
Comeau
Steven F
SF
Ziegler
Thomas A
TA
Wynn
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse