Bock Cristin N, Babu Subash, Breloer Minka, Rajamanickam Anuradha, Boothra Yukhti, Brunn Marie-Luise, Kühl Anja A, Merle Roswitha, Löhning Max, Hartmann Susanne, Rausch Sebastian
Department of Veterinary Medicine, Institute of Immunology, Freie Universität BerlinBerlin, Germany.
National Institutes of Health-NIRT-International Center for Excellence in ResearchChennai, India.
Front Cell Infect Microbiol. 2017 Jun 20;7:261. doi: 10.3389/fcimb.2017.00261. eCollection 2017.
Infections by the soil-transmitted threadworm affect 30-100 million people worldwide, predominantly in tropic and sub-tropic regions. Here we assessed the T helper cell phenotypes in threadworm-infected patients and experimental murine infections with focus on CD4 T cells co-expressing markers of Th2 and Th1 differentiation. We show that mice infected with the close relative generate strong Th2 responses characterized by the expansion of CD4 GATA-3 cells expressing IL-4/-5/-13 in blood, spleen, gut-draining lymph nodes, lung and gut tissue. In addition to conventional Th2 cells, significantly increased frequencies of GATA-3T-bet Th2/1-hybrid cells were detected in all organs and co-expressed Th2- and Th1-cytokines at intermediate levels. Assessing the phenotype of blood-derived CD4 T cells from South Indian patients infected with and local uninfected control donors we found that GATA-3 expressing Th2 cells were significantly increased in the patient cohort, coinciding with elevated eosinophil and IgE/IgG4 levels. A fraction of IL-4CD4 T cells simultaneously expressed IFN-γ hence displaying a Th2/1 hybrid phenotype. In accordance with murine Th2/1 cells, human Th2/1 cells expressed intermediate levels of Th2 cytokines. Contrasting their murine counterparts, human Th2/1 hybrids were marked by high levels of IFN-γ and rather low GATA-3 expression. Assessing the effector function of murine Th2/1 cells we found that Th2/1 cells were qualified for driving the classical activation of macrophages. Furthermore, Th2/1 cells shared innate, cytokine-driven effector functions with Th1 cells. Hence, the key findings of our study are that T helper cells with combined characteristics of Th2 and Th1 cells are integral to immune responses of helminth-infected mice, but also occur in helminth-infected humans and we suggest that Th2/1 cells are poised for the instruction of balanced immune responses during nematode infections.
土源性线虫感染在全球影响着3000万至1亿人，主要分布在热带和亚热带地区。在此，我们评估了线虫感染患者和实验性小鼠感染中的辅助性T细胞表型，重点关注共表达Th2和Th1分化标志物的CD4 T细胞。我们发现，感染相近线虫的小鼠产生强烈的Th2反应，其特征是血液、脾脏、肠道引流淋巴结、肺和肠道组织中表达IL-4/-5/-13的CD4 GATA-3细胞扩增。除了传统的Th2细胞外，在所有器官中均检测到GATA-3T-bet Th2/1杂交细胞的频率显著增加，且这些细胞以中等水平共表达Th2和Th1细胞因子。评估来自南印度感染线虫患者和当地未感染对照供体的血液来源CD4 T细胞表型，我们发现患者队列中表达GATA-3的Th2细胞显著增加，同时嗜酸性粒细胞以及IgE/IgG4水平升高。一部分IL-4 CD4 T细胞同时表达IFN-γ，因此呈现出Th2/1杂交表型。与小鼠Th2/1细胞一致，人Th2/1细胞表达中等水平的Th2细胞因子。与小鼠对应细胞不同的是，人Th2/1杂交细胞以高水平的IFN-γ和相当低的GATA-3表达为特征。评估小鼠Th2/1细胞的效应功能，我们发现Th2/1细胞具备驱动巨噬细胞经典活化的能力。此外，Th2/1细胞与Th1细胞共享固有、细胞因子驱动的效应功能。因此，我们研究的关键发现是，具有Th2和Th1细胞组合特征的辅助性T细胞是蠕虫感染小鼠免疫反应不可或缺的一部分，也存在于蠕虫感染的人类中，并且我们认为Th2/1细胞在指导线虫感染期间的平衡免疫反应中发挥作用。
