Moore Tyler C, Gonzaga Lorena M, Mather Jennifer M, Messer Ronald J, Hasenkrug Kim J
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
mBio. 2017 Aug 1;8(4):e01122-17. doi: 10.1128/mBio.01122-17.
Regulatory T cells (Tregs) are immunosuppressive cells of the immune system that control autoimmune reactivity. Tregs also respond during immune reactions to infectious agents in order to limit immunopathological damage from potent effectors such as CD8 cytolytic T lymphocytes. We have used the Friend virus (FV) model of retroviral infection in mice to investigate how viral infections induce Tregs. During acute FV infection, there is significant activation and expansion of thymus-derived (natural) Tregs that suppress virus-specific CD8 T cell responses. Unlike conventional T cells, the responding Tregs are not virus specific, so the mechanisms that induce their expansion are of great interest. We now show that B cells provide essential signals for Treg expansion during FV infection. Treg responses are greatly diminished in B cell-deficient mice but can be restored by adoptive transfers of B cells at the time of infection. The feeble Treg responses in B cell-deficient mice are associated with enhanced virus-specific CD8 T cell responses and accelerated virus control during the first 2 weeks of infection. experiments demonstrated that B cells promote Treg activation and proliferation through a glucocorticoid-induced receptor superfamily member 18 (GITR) ligand-dependent mechanism. Thus, B cells play paradoxically opposing roles during FV infection. They provide proliferative signals to immunsosuppressive Tregs, which slows early virus control, and they also produce virus-specific antibodies, which are essential for long-term virus control. When infectious agents invade a host, numerous immunological mechanisms are deployed to limit their replication, neutralize their spread, and destroy the host cells harboring the infection. Since immune responses also have a strong capacity to damage host cells and tissues, their magnitude, potency, and duration are under regulatory control. Regulatory T cells are an important component of this control, and the mechanisms that induce them to respond and exert immunosuppressive regulation are of great interest. In the current report, we show that B cells, the cells responsible for making pathogen-specific antibodies, are also involved in promoting the expansion of regulatory T cells during a retroviral infection. studies demonstrated that they do so via stimulation of the Tregs through interactions between cell surface molecules: GITR interactions with its ligand (GITRL) on B cells and GITR on regulatory T cells. These findings point the way toward therapeutics to better treat infections and autoimmune diseases.
调节性T细胞（Tregs）是免疫系统中的免疫抑制细胞，可控制自身免疫反应。在免疫反应过程中，Tregs也会对感染因子作出反应，以限制来自如CD8细胞溶解性T淋巴细胞等强效效应细胞的免疫病理损伤。我们利用小鼠逆转录病毒感染的弗氏病毒（FV）模型来研究病毒感染如何诱导Tregs。在急性FV感染期间，胸腺来源的（天然）Tregs会发生显著激活和扩增，从而抑制病毒特异性CD8 T细胞反应。与传统T细胞不同，应答的Tregs并非病毒特异性的，因此诱导其扩增的机制备受关注。我们现在表明，B细胞在FV感染期间为Treg扩增提供关键信号。在B细胞缺陷小鼠中，Treg反应大大减弱，但在感染时通过B细胞的过继转移可以恢复。B细胞缺陷小鼠中微弱的Treg反应与感染最初2周内增强的病毒特异性CD8 T细胞反应和加速的病毒控制有关。实验表明，B细胞通过糖皮质激素诱导的受体超家族成员18（GITR）配体依赖性机制促进Treg激活和增殖。因此，B细胞在FV感染期间发挥着看似矛盾的相反作用。它们为免疫抑制性Tregs提供增殖信号，这减缓了早期病毒控制，同时它们也产生病毒特异性抗体，这对长期病毒控制至关重要。当感染因子侵入宿主时，会部署多种免疫机制来限制其复制、中和其传播并破坏携带感染的宿主细胞。由于免疫反应也具有强大的损伤宿主细胞和组织的能力，因此它们的强度、效力和持续时间受到调节控制。调节性T细胞是这种控制的重要组成部分，诱导它们作出反应并发挥免疫抑制调节的机制备受关注。在本报告中，我们表明，负责产生病原体特异性抗体的B细胞也参与在逆转录病毒感染期间促进调节性T细胞的扩增。研究表明，它们通过细胞表面分子之间的相互作用刺激Tregs来实现这一点：B细胞上的GITR与其配体（GITRL）以及调节性T细胞上的GITR之间的相互作用。这些发现为更好地治疗感染和自身免疫性疾病的疗法指明了方向。
