Cellular Immunity to Phages
细胞对噬菌体的免疫
Phages also elicit cellular adaptive immunity. When phages are endocytosed and processed by APCs, phage-derived peptides are presented on MHC surface molecules, resulting in B and T cell responses against the relevant viral antigen in vitro (127, 128) and in vivo (93, 129). For example, E. coli fd phage engineered to express a peptide antigen is taken up by phagocytes and presented on both cell-surface MHC-I and MHC-II molecules, resulting in CD8+ and CD4+ T cell responses, respectively (127, 128). Moreover, phages can stimulate the secretion of costimulatory molecules required for T cell activation (99). Cytotoxic CD8+ T cell responses elicited using phage display vaccines target eukaryotic virus-infected cells (140) and tumors (141).
噬菌体还能引起细胞适应性免疫。当噬菌体被APCs内吞和处理时，噬菌体衍生的肽会呈现在MHC表面分子上，从而在体外（127、128）和体内（93、129）产生针对相关病毒抗原的B细胞和T细胞反应。例如，表达肽抗原的大肠杆菌噬菌体被吞噬细胞吸收，并呈现在细胞表面的 MHC-I 和 MHC-II 分子上，分别产生 CD8 + 和 CD4 + T 细胞应答（127）。分别产生 CD8 + 和 CD4 + T 细胞反应 ( 127, 128)。此外，噬菌体还能刺激 T 细胞活化所需的激动分子的分泌（99）。细胞毒性 CD8 + 细胞毒性 CD8 {{2} T 细胞反应是利用噬菌体展示疫苗针对真核病毒感染细胞（140）和肿瘤（141）诱发的。
Phages also prime CD4+ Th cell immunity. There are reports of both Th1 and Th2 responses by phages in T cell line stimulation assays in vitro (142–144) and by phage vaccines in vivo (97, 98). Research with phiX174 indicates that T cell help is critical in developing the initial B cell IgM phage-specific response, as well as in class-switching to IgG (145).
噬菌体还能激发 CD4 + Th 细胞免疫。Th 细胞免疫。有报告称，噬菌体在体外 T 细胞系刺激试验（142- 144）和体内噬菌体疫苗（97、98）中都产生了 Th1 和 Th2 反应。对 phiX174 的研究表明，T 细胞的帮助对形成最初的 B 细胞 IgM 噬菌体特异性反应以及向 IgG 的类别转换至关重要 ( 145)。
There are indications that endogenous phages may likewise be involved in the education of T cells and anticancer immunity. Fluckiger et al. (146) recently described MHC-I restricted epitopes in a prophage present in Enterococcus hirae that stimulate a CD8+ T lymphocyte response against a cross-reactive tumor-associated antigen, tape measure protein (TMP). Upon immunotherapy with cyclophosphamide or anti–programmed death-1 (PD-1) antibodies, mice bearing E. hirae harboring this prophage mounted a TMP-specific cytotoxic T-lymphocyte response, resulting in tumor clearance. Moreover, in human renal and lung cancer patients, the presence of the enterococcal prophage and expression of TMP by tumors correlated with long-term benefit of PD-1 blockade therapy. These exciting results suggest that antitumor immunity may be influenced by both the phageome and immunomodulatory therapies that affect responses to these antigens. Further investigation of the tumor phageome in patients and how composition and abundance associate with cancer outcome is necessary in order to fully explore this field. These findings may also be relevant to other aspects of cellular immunity and the microbiome. One might anticipate that autoimmunity associated with PD-1 blockade might likewise be affected by similar dynamics.
有迹象表明，内源性噬菌体也可能参与 T 细胞教育和抗癌免疫。Fluckiger 等人（146）最近描述了平肠球菌噬菌体中存在的 MHC-I 限制表位，它能刺激 CD8 {{0} T 淋巴细胞对交叉反应性肿瘤相关抗原（tape measure protein，胶带测量蛋白）产生反应。T淋巴细胞对交叉反应性肿瘤相关抗原–胶带测量蛋白（TMP）的反应。在使用环磷酰胺或抗程序性死亡-1（PD-1）抗体进行免疫治疗时，携带这种噬菌体的小鼠会产生针对 TMP 的特异性细胞毒性 T 淋巴细胞反应，从而清除肿瘤。此外，在人类肾癌和肺癌患者中，肠球菌噬菌体的存在和肿瘤中 TMP 的表达与 PD-1 阻断疗法的长期获益相关。这些令人兴奋的结果表明，抗肿瘤免疫力可能受到噬菌体组和影响对这些抗原反应的免疫调节疗法的双重影响。有必要进一步调查患者体内的肿瘤噬菌体组，以及噬菌体组的组成和丰度如何与癌症结果相关联，以便全面探索这一领域。这些发现也可能与细胞免疫和微生物组的其他方面有关。我们可以预见，与 PD-1 阻断相关的自身免疫也会受到类似动态的影响。
A Model for Tri-Kingdom Interactions Between Bacteria, Bacteriophages, and Their Human Hosts
细菌、噬菌体及其人类宿主之间的三界互动模型
In recent years a tremendous body of work has yielded exciting insights into the role of commensal bacteria in directing host health and development. In particular, studies have demonstrated a profound influence of the microbiota on host immunity and metabolism with reverberant effects on commensal composition and structure. With the exception of a few studies, the role of bacteriophages in contributing to this dynamic has largely been overlooked.
近年来，大量研究工作使人们对共生细菌在引导宿主健康和发育方面的作用有了令人兴奋的认识。特别是，研究表明微生物群对宿主的免疫和新陈代谢有着深远的影响，并对共生菌的组成和结构产生反响。除少数研究外，噬菌体在这种动态变化中的作用在很大程度上被忽视了。
The data reviewed here offer tantalizing indications of the importance of bacteriophages to human biology. Not only do phages influence our cells and tissues indirectly via effects on their bacterial hosts, but also they directly affect the immune response to bacteria. In a sense then, phages shape the interface between our immunologic and bacterial selves.
本文回顾的数据提供了噬菌体对人类生物学重要性的诱人迹象。噬菌体不仅通过对细菌宿主的影响间接影响我们的细胞和组织，而且还直接影响对细菌的免疫反应。从某种意义上说，噬菌体塑造了我们的免疫系统和细菌系统之间的界面。
We propose that our interactions with our microbiome are perhaps best understood as an interconnected network of bacteria, bacteriophages, and human cells (Figure 1). Tri-kingdom interactions between these individual components may govern the stability of the network as a whole. For example, phages potentially restrict bacterial expansion and overgrowth, thereby limiting inflammation at sites of colonization. Conversely, through direct and indirect modulation of host immunity, phages may promote immunologic tolerance to commensal colonization. The disruption of this balance, through exposure to exogenous phages, microbial dysbiosis, or immune dysregulation, may have significant consequences for our immunologic and metabolic health.
我们认为，我们与微生物组之间的互动最好理解为由细菌、噬菌体和人体细胞组成的相互关联的网络（图 1）。这些单个组成部分之间的三界互动可能会影响整个网络的稳定性。例如，噬菌体可能会限制细菌的扩张和过度生长，从而限制定植部位的炎症。相反，通过直接或间接调节宿主免疫，噬菌体可能会促进对共生菌定植的免疫耐受。通过接触外源噬菌体、微生物菌群失调或免疫调节失调来破坏这种平衡，可能会对我们的免疫和代谢健康产生重大影响。
Unfortunately, the existing data on these interactions and the options remain limited. Most of the relevant literature involves a limited number of phages. Many of these have been extensively modified phages for use as lytic phage therapy or in biotechnology. It will be important to expand on this research with commensal (unmodified) phages studied in the context of both steady-state and inflammatory conditions. In addition, the existing methodologies are often poorly suited for investigating the physiologic effect of phages in vivo. Capturing information on prophages as well as free phage particles and on phages within cells and tissues will be critical to these efforts. There have been exciting advances in computational biology, but our ability to elucidate phage biology from sequence data likewise remains a work in progress. Finally, most of our information is from mice; well-controlled, rigorous studies in human subjects will be essential to understanding the effect of phages on human immunity.
遗憾的是，有关这些相互作用和选择的现有数据仍然有限。大多数相关文献涉及数量有限的噬菌体。其中许多噬菌体已被广泛改造，用于溶菌噬菌体疗法或生物技术。在稳态和炎症条件下对共生（未修饰）噬菌体进行研究，对扩展这方面的研究非常重要。此外，现有的方法往往不适合研究噬菌体在体内的生理效应。捕捉原噬菌体、游离噬菌体颗粒以及细胞和组织内噬菌体的信息对这些研究工作至关重要。计算生物学取得了令人振奋的进步，但我们从序列数据中阐明噬菌体生物学的能力同样仍在不断进步。最后，我们的大部分信息都来自小鼠；要想了解噬菌体对人体免疫力的影响，必须对人体进行严格的控制和研究。
The potential benefits of optimizing these efforts are great. By developing methods to more effectively study our endogenous phages, we will be able to elaborate on these tri-kingdom interactions and perhaps gain profound insights into human health and disease.
优化这些工作的潜在好处是巨大的。通过开发更有效地研究内源噬菌体的方法，我们将能够详细阐述这些三界相互作用，或许还能获得有关人类健康和疾病的深刻见解。