Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Nature. 2011 Aug 14;477(7363):229-33. doi: 10.1038/nature10329.
CD4(+) T-helper type 2 (T(H)2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9 and IL-13, are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, indicating that TSLP is a critical regulator of T(H)2 cytokine-associated inflammatory diseases. In support of genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes T(H)2 cytokine-mediated immunity and inflammation. However, the mechanisms through which TSLP induces T(H)2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses, and that TSLPR-sufficient basophils can restore T(H)2-cell-dependent immunity in vivo. TSLP acted directly on bone-marrow-resident progenitors to promote basophil responses selectively. Critically, TSLP could elicit basophil responses in both IL-3-IL-3R-sufficient and -deficient environments, and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Furthermore, activated human basophils expressed TSLPR, and basophils isolated from eosinophilic oesophagitis patients were distinct from classical basophils. Collectively, these studies identify previously unrecognized heterogeneity within the basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil haematopoiesis and eliciting a population of functionally distinct basophils that promote T(H)2 cytokine-mediated inflammation.
CD4(+) T 辅助细胞 2 型（T(H)2）细胞，其特征是表达白细胞介素（IL）-4、IL-5、IL-9 和 IL-13，是对蠕虫寄生虫免疫所必需的，并促进与哮喘和过敏性疾病相关的病理性炎症。编码细胞因子胸腺基质淋巴细胞生成素（TSLP）的基因中的多态性与人类多种过敏性疾病的发展有关，表明 TSLP 是 T(H)2 细胞因子相关炎症性疾病的关键调节剂。支持遗传分析，在患者中，TSLP 的过度产生与哮喘、特应性皮炎和食物过敏有关，并且在鼠系统中的研究表明，TSLP 促进 T(H)2 细胞因子介导的免疫和炎症。然而，TSLP 诱导 T(H)2 细胞因子反应的机制仍未得到明确。在这里，我们证明 TSLP 促进全身性嗜碱性粒细胞增多，TSLP-TSLPR 相互作用的破坏导致嗜碱性粒细胞反应缺陷，并且 TSLPR 足够的嗜碱性粒细胞可以在体内恢复 T(H)2 细胞依赖性免疫。TSLP 直接作用于骨髓驻留祖细胞，选择性地促进嗜碱性粒细胞反应。至关重要的是，TSLP 可以在 IL-3-IL-3R 充足和缺乏的环境中引发嗜碱性粒细胞反应，并且全基因组转录谱和功能分析确定了 TSLP 诱导的嗜碱性粒细胞与 IL-3 诱导的嗜碱性粒细胞之间的异质性。此外，激活的人嗜碱性粒细胞表达 TSLPR，并且从嗜酸性食管炎患者中分离的嗜碱性粒细胞与经典嗜碱性粒细胞不同。总之，这些研究确定了嗜碱性粒细胞谱系内以前未被识别的异质性，并表明 TSLP 的表达可能通过调节嗜碱性粒细胞造血和引发促进 T(H)2 细胞因子介导的炎症的功能不同的嗜碱性粒细胞群体来影响多种过敏性疾病的易感性。
