PDF(Pubmed)
Abstract：
Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell-autologous mechanism to prevent such damage. However, IL-10-producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. This work provides insights into the development and function of CD4+ T cells during protozoan parasitic infections and identifies key immunoregulatory molecules.
摘要：
内脏利什曼病（VL）的控制取决于促炎Th1细胞，该细胞可激活感染的组织巨噬细胞以杀死常驻的细胞内寄生虫。然而,Th1细胞产生的促炎细胞因子会损伤组织，需要严格的调节。Th1细胞IL-10的产生是防止这种损伤的重要的细胞自体机制。然而,产生IL-10的Th1(1型调节;Tr1)细胞还可以延迟药物治疗或疫苗接种后寄生虫的控制和免疫的产生。为了确定靶向分子，以改变Th1和Tr1细胞之间的平衡，以提高抗寄生虫免疫力，我们比较了利什曼原虫感染C57BL/6J小鼠实验性VL中Th1和Tr1细胞的分子和表型特征。我们还通过比较来自具有实验性VL和疟疾的小鼠的Tr1细胞的转录谱来鉴定共有的Tr1细胞原生动物特征。我们确定LAG3是VL和实验性VL患者的重要共抑制受体，我们揭示了Tr1细胞共抑制受体表达的组织特异性异质性。我们还发现转录因子Pbx1在抑制CD4T细胞细胞因子产生中的作用。这项工作提供了对原生动物寄生虫感染期间CD4+T细胞的发育和功能的见解，并确定了关键的免疫调节分子。
