Taylor Betsy C, Zaph Colby, Troy Amy E, Du Yurong, Guild Katherine J, Comeau Michael R, Artis David
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Exp Med. 2009 Mar 16;206(3):655-67. doi: 10.1084/jem.20081499. Epub 2009 Mar 9.
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.
肠道上皮细胞（IECs）可产生胸腺基质淋巴细胞生成素（TSLP）；然而，TSLP与TSLP受体（TSLPR）相互作用对肠道免疫和炎症的体内影响仍不清楚。我们发现TSLP与TSLPR的相互作用对于抵抗肠道病原体鞭虫的免疫反应至关重要。在正常具有抗性的小鼠中，单克隆抗体介导的TSLP中和或TSLPR缺失导致Th2细胞因子表达缺陷和持续性感染。易感性伴随着白细胞介素（IL）12/23p40、干扰素（IFN）γ和IL-17A表达升高，以及严重肠道炎症的发展。至关重要的是，在感染鞭虫的TSLPR基因敲除小鼠中中和IFN-γ可恢复Th2细胞因子反应并导致蠕虫排出，这首次证明了存在不依赖TSLPR的Th2细胞因子产生途径。此外，TSLPR基因敲除小鼠表现出IL-12/23p40和IFN-γ产生增加，并在暴露于葡聚糖硫酸钠后出现肠道炎症加剧，这表明在炎症性肠病小鼠模型中TSLP具有先前未被认识的免疫调节作用。
