Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom.
J Immunol. 2011 Aug 1;187(3):1411-20. doi: 10.4049/jimmunol.1100834. Epub 2011 Jun 24.
The immune suppression that characterizes human helminth infections can hinder the development of protective immunity or help to reduce pathogenic inflammation. Signaling through the T cell costimulator glucocorticoid-induced TNFR-related protein (GITR) counteracts immune downregulation by augmenting effector T cell responses and abrogating suppression by Foxp3(+) regulatory T cells. Thus, superphysiological Ab-mediated GITR costimulation represents a novel therapy for promoting protective immunity toward parasitic helminths, whereas blocking physiological GITR-GITR ligand (GITRL) interactions may provide a mechanism for dampening pathogenic Th2 inflammation. We investigated the superphysiological and physiological roles of the GITR-GITRL pathway in the development of protective and pathogenic Th2 responses in murine infection models of filariasis (Litomosoides sigmodontis) and schistosomiasis (Schistosoma mansoni). Providing superphysiological GITR costimulation using an agonistic anti-GITR mAb over the first 12 d of L. sigmodontis infection initially increased the quantity of Th2 cells, as well as their ability to produce Th2 cytokines. However, as infection progressed, the Th2 responses reverted to normal infection levels, and parasite killing remained unaffected. Despite the Th2-promoting role of superphysiological GITR costimulation, Ab-mediated blockade of the GITR-GITRL pathway did not affect Th2 cell priming or maintenance during L. sigmodontis infection. Blockade of GITR-GITRL interactions during the acute egg phase of S. mansoni infection resulted in reduced Th2 responses, but this effect was confined to the spleen and did not lead to changes in liver pathology. Thus, although superphysiological GITR costimulation can therapeutically enhance Th2 responses, physiological GITR-GITRL interactions are not required for the development of Th2-mediated resistance or pathology in murine models of filariasis and schistosomiasis.
人类寄生虫感染的特征是免疫抑制，这可能会阻碍保护性免疫的发展，或有助于减轻致病炎症。通过 T 细胞共刺激物糖皮质激素诱导的 TNFR 相关蛋白（GITR）的信号传导，通过增强效应 T 细胞反应和废除 Foxp3(+)调节性 T 细胞的抑制作用，来对抗免疫下调。因此，超生理 Ab 介导的 GITR 共刺激代表了一种促进针对寄生虫蠕虫保护性免疫的新型治疗方法，而阻断生理性 GITR-GITRL 相互作用可能为抑制致病 Th2 炎症提供一种机制。我们研究了 GITR-GITRL 途径在丝虫病（Litomosoides sigmodontis）和血吸虫病（Schistosoma mansoni）的鼠类感染模型中保护性和致病性 Th2 反应发展中的超生理和生理作用。在 L. sigmodontis 感染的前 12 天内，使用激动性抗 GITR mAb 提供超生理 GITR 共刺激作用最初增加了 Th2 细胞的数量及其产生 Th2 细胞因子的能力。然而，随着感染的进展，Th2 反应恢复到正常感染水平，并且寄生虫杀伤仍然不受影响。尽管超生理 GITR 共刺激作用具有促进 Th2 的作用，但 Ab 介导的 GITR-GITRL 途径阻断在 L. sigmodontis 感染期间并不影响 Th2 细胞的启动或维持。在 S. mansoni 感染的急性卵期阻断 GITR-GITRL 相互作用导致 Th2 反应减少，但这种作用仅限于脾脏，不会导致肝脏病理变化的改变。因此，尽管超生理 GITR 共刺激作用可以治疗性地增强 Th2 反应，但在丝虫病和血吸虫病的鼠类模型中，生理性 GITR-GITRL 相互作用不是 Th2 介导的抗性或病理学发展所必需的。
