Cytokine regulation of anti-helminth immunity

描述（由申请人提供）：全世界估计有20亿人感染了土壤传播的寄生虫，这类寄生虫感染是一个重大的公共卫生和经济问题。虽然以IL-4和IL-13产生为特征的CD4+ T辅助型2 （TH2）细胞应答是对肠道蠕虫感染的保护性免疫所必需的，但体内促进TH2细胞应答的先天免疫应答尚不完全清楚。本研究的目的是探讨上皮细胞来源的细胞因子胸腺基质淋巴生成素（TSLP）对调节嗜碱性粒细胞反应和TSLP应答性祖细胞群分化的影响，并评估这些细胞在肠线虫感染后影响TH2细胞因子依赖的宿主保护性免疫中的作用。利用鼠Trichuris和旋毛虫这两种具有良好特征的人类蠕虫感染实验小鼠模型，我们的初步研究发现，TSLP选择性地促进嗜碱性细胞反应，嗜碱性细胞限制性表达足以部分恢复易感小鼠蠕虫感染后的TH2细胞反应和宿主保护性免疫。此外，我们在外周发现了一群TSLP诱导的祖细胞样细胞，它们表达TSLP受体（TSLPR），表现出多能潜能，并分化为产生IL-4和IL-13的效应细胞。总的来说，这些数据提供了两种以前未被认识的途径，通过这些途径，tslp依赖性嗜碱性粒细胞和外周祖细胞样群体是抗蠕虫免疫的关键调节因子。采用一系列新颖的过继转移和体内耗竭方法，本提案的第1部分将利用小鼠实验Trichuris或旋毛虫感染来确定TSLP如何调节宿主保护性免疫所需的先天免疫反应。本提案的目标2将利用类似的小鼠过继性转移研究，结合人类患者和人源化小鼠（hu-mice）的前沿研究，评估TSLP对外周祖细胞反应的影响。这些研究的结果将为测试操纵tslp诱导的嗜碱性细胞或tslp诱导的祖样细胞在促进抗蠕虫免疫中的治疗潜力提供一个框架。我们预计，确定tslp诱导的嗜碱性细胞和祖细胞样细胞对抗寄生虫免疫的贡献将指导未来设计和提高抗寄生虫口服疫苗的功效，并抑制哮喘和其他过敏性疾病中TH2细胞因子相关的炎症。

DESCRIPTION (provided by applicant): With an estimated two billion people infected with soil-transmitted helminthes worldwide, this group of parasitic infections represents a significant public health and economic concern. While CD4+ T helper type 2 (TH2) cell responses characterized by IL-4 and IL-13 production are required for protective immunity to intestinal helminth infection, the innate immune responses that promote TH2 cell responses in vivo remain incompletely understood. The goals of this proposal are to interrogate the influence of the epithelial cell-derived cytokine thymic stromal lymphopoietin (TSLP) on regulating basophil responses and the differentiation of TSLP- responsive progenitor cell populations and to assess the role of these cells in influencing TH2 cytokine- dependent host protective immunity following intestinal nematode infection. Employing Trichuris muris and Trichinella spiralis, two well-characterized experimental murine models of human helminth infections, our preliminary studies identified that TSLP selectively promotes basophil responses and basophil-restricted expression was sufficient to partially restore TH2 cell responses and host protective immunity following helminth infection in susceptible mice. In addition, we identified a population of TSLP-elicited progenitor-like cells in the periphery that express the TSLP receptor (TSLPR), exhibit multipotent potential and differentiate to effector cells that produce IL-4 and IL-13. Collectively these data provide insight into two previously unrecognized pathways by which TSLP-dependent basophils and peripheral progenitor-like populations are critical regulators of anti-helminth immunity. Employing a series of novel adoptive transfers and in vivo depletion approaches, Aim 1 of this proposal will utilize experimental Trichuris or Trichinella infection in mice to determine how TSLP regulates innate immune responses required for host protective immunity. Aim 2 of this proposal will utilize similar adoptive transfer studies in mice, in conjunction with cutting edge studies in human patients and humanized mice (hu-mice), to assess the influence of TSLP on progenitor cell responses in the periphery. The results of these studies will provide a framework to test the therapeutic potential of manipulating TSLP-elicited basophils or TSLP-elicited progenitor-like cells in the promotion of anti-helminth immunity. We anticipate that defining the contribution of TSLP-elicited basophils and progenitor-like cells to anti-helminth immunity will direct future efforts to design and improve the efficacy of anti-parasitic oral vaccines and to dampen TH2 cytokine-associated inflammation in the context of asthma and other allergic diseases.