Th2 memory responses to an intestinal helminth infection

目前的资助期揭示了针对肠道线虫的Th2记忆的三个主要方面：(i)腹膜在原发性感染消除后维持记忆Th2细胞中起关键作用；（ii）使用蠕虫排泄/分泌（E/S）产物免疫可诱导类似于自然感染的保护水平，以防止再次感染，这特别依赖于长寿命的功能记忆T细胞；（iii） Th2记忆细胞的形成、组织分布和回忆反应与宿主微生物群无关。基于这些发现，我们的目标是扩大对肠道蠕虫延长期Th2记忆细胞募集和再激活机制的认识。以下假设将被研究：A)腹膜对于效应和记忆Th2细胞的再循环至关重要，从而对肠道线虫产生保护性免疫反应。这将通过a)过性转移来确定腹膜记忆Th2细胞是否在再次感染线虫后迁移到小肠；b)阻断细胞粘附标记来解释它们的相互作用是否对腹膜Th2细胞的募集、保留和重新定位至关重要。B)细胞因子环境和腹腔内局部抗原呈递是Th2记忆细胞再激活的必要条件。在这里，我们计划关注IL-27作为腹膜中Th2记忆细胞形成和再激活的调节因子的作用，并研究感染后腹膜中Th2记忆细胞的再激活是否是一个抗原依赖的过程。C)肠系膜脂肪是肠线虫感染中Th2记忆细胞的重要储存库，并促进对寄生虫E/S产物的保护性免疫反应。根据初步数据显示，肠系膜脂肪在原发感染线虫一年多后仍含有Th2记忆细胞，我们旨在揭示在胃肠道线虫的原发感染、记忆阶段、再感染以及肠道线虫E/S产物免疫后，Th2细胞是否与脂肪细胞相互作用。

The current funding period revealed three main aspects of Th2 memory against intestinal nematodes: (i) the peritoneum plays a key role in the maintenance of memory Th2 cells after abrogation of primary infection; (ii) immunization with helminth excretory/secretory (E/S) products induces a level of protection similar to that of natural infection against reinfection, which specifically depends on long-lived functional memory T cells; (iii) Th2 memory cell formation, tissue distribution, and recall response are independent of host microbiota. Based on these findings, we aim to expand the knowledge of the mechanisms of Th2 memory cell recruitment and reactivation against intestinal helminths in the prolongation phase. The following hypotheses will be investigated: A) The peritoneum is essential for the recirculation of effector and memory Th2 cells for a protective immune response against intestinal nematodes. This will be investigated by a) adoptive transfers to determine whether peritoneal memory Th2 cells migrate to the small intestine upon re-infection with nematodes and b) blocking cellular adhesion markers to decipher whether their interaction is essential for recruitment, retention and relocalization of peritoneal Th2 cells. B) Cytokine environment and local antigen presentation in the peritoneal cavity are essential for Th2 memory cell reactivation. Here, we plan to focus on the role of IL-27 as a regulator of Th2 memory cell formation and reactivation in the peritoneum and to investigate whether the reactivation of Th2 memory cells in the peritoneum after infection is an antigen-dependent process. C) Mesenteric fat is an important reservoir of Th2 memory cells in intestinal nematode infections and promotes protective immune responses against parasite E/S products. Based on preliminary data showing that mesenteric fat contains Th2 memory cells more than a year after primary nematode infection, we aim to decipher whether Th2 cells interact with adipocytes during primary infection, memory stage, and reinfection with gastrointestinal nematodes and after immunization with E/S products of intestinal nematodes.