Decades of discovery have led immunologists to compartmentalize the mammalian immune system into two components: innate and adaptive immunity. The textbooks and traditional viewpoint describe the innate immune system as rapid and non-specific, whereas the adaptive immune system consisting of T and B cells is delayed but specific and possessing memory. Every immune cell type that is not a T or B cell is broadly lumped under the umbrella of innate immunity. However, recent research has shown us that certain innate immune cells can possess features of adaptive immunity, including immunological memory.

Anecdotal evidence of memory in the innate immune system—a memory independent of T and B cell-mediated antigen-specific memory—has existed for a century or more and included observations in plants and animals, including humans. Only recently, however, have the specific cellular and molecular mechanisms started to emerge, highlighting fundamentals of immunity and previously unknown functional ‘levers’ that tune immune tone. The key cellular players, natural killer (NK) cells and myeloid cells, are found at the forefront of this paradigm-shifting revolution and central to this volume of Immunological Reviews. Two decades ago, NK cells were first shown to possess adaptive immune features from antigen specificity to clonal expansion to long-lived memory to recall responses. Next, myeloid cells were proposed to possess anamnestic responses after initial stimulation in a process termed “trained immunity.” Although our understanding of the mechanisms driving such adaptive characteristics in innate immune cells has expanded in recent years, there is still much to be learned about the important features of innate immune memory. Future studies will illuminate additional external signals inducing durable memory, cellular and metabolic processes required, underlying transcription factor and epigenetic programs and their durability, and finally the impact on health and disease.

The first group of reviews in this volume address how mouse and human NK cells respond to various environmental stimuli that program their clonality, gene expression, metabolism, effector function, survival, trafficking, tissue residency, and memory. Reviews from Delconte and Sun¹ and Ashkar and colleagues,² focus on underlying organ-specific metabolic mechanisms in mouse and human NK cells, respectively, in the contexts of nutrition and health versus host perturbations including fasting, infection, and cancer. Aguilar and Lanier³ highlight how adaptive features of NK cells including clonal expansion depend upon specific signaling via ITAM-containing receptors. Reviews from Degli-Esposti and colleagues,⁴ Hermans and O'Sullivan,⁵ and Ruckert and Romagnani⁶ focus on the selection of mouse and human NK cell clones to be epigenetically primed for effector function and survival during their response against cytomegalovirus infection, where the subsequent memory NK cells can become resident in certain tissues to protect against autoimmunity and secondary infection.

A second group of reviews centers around how innate lymphoid cells (ILC) can possess heterogeneity, plasticity, and memory following exposure to specific inflammatory signals. Colonna and colleagues⁷ review how group 1 ILCs (ILC1) are distinct from NK cells and driven by shared and unique transcription factors to reside as sentinels embedded and resident in tissues. Martinez-Gonzalez and Takei⁸ summarize how group 2 ILCs (ILC2) can mediate allergic recall responses following type 2 cytokine exposure and how ILC2 memory can result in both beneficial and deleterious effects on health. Serafini and Di Santo⁹ discuss how group 3 ILCs (ILC3) can be primed in intestinal tissue to possess memory during bacteria-driven inflammation and the consequences of ILC3 priming. All reviews in this group point out that ILC1, ILC2, and ILC3 heterogeneity has been recently revealed using various single-cell sequencing approaches.

In addition to NK cells and ILCs, which lack germline-rearranged antigen receptors, innate T cells are also included in a third group of reviews that focus on mucosal-associated invariant T cells (MAIT) and tumor-associated innate T lymphocytes. Prlic and colleagues¹⁰ focus on the functions of MAIT cells in healthy versus inflamed tissues and discuss the TCR and cytokine signals that this subset of innate T cells integrates when activated. Li and colleagues¹¹ describe a subset of innate T cells with cytotoxic potential that are distinct from conventional T cells but are similarly recruited to tumors and provide an important cancer immunosurveillance function.

One common feature of these lymphoid lineage innate (and innate-like) immune cells described above is their shared potential for clonal expansion, a potent and inherently memory-forming characteristic if these cells persist, especially with acquired type-specific inflammatory programs. In contrast, cells of the myeloid lineage generally lack the potential for extensive expansion. Despite this, myeloid cells have a commanding ability to initiate and control immune responses as a result of their potential to robustly initiate inflammatory cascades, recruit diverse other immune cells, and present antigen to T cells and the innate lymphoid cells. In recent years, it has become clear that these powerful immune kickstarting activities in myeloid cells are subject to durable epigenetic and metabolic tuning following inflammatory challenges. These altered myeloid phenotypes can substantively change immune function across a spectrum from bolstering defense to driving or exacerbating inflammatory pathology.

One ostensible paradox in the field has been that many of these myeloid cells that mediate durable innate immune memory are themselves short-lived. Recent studies reviewed and elaborated in this issue highlight the critical role of myeloid progenitor cells and self-renewing hematopoietic stem cells (HSC) as a major cellular reservoir of inflammatory memory capable of passing epigenetic programs to mature progeny myeloid cells. Netea and colleagues¹² comprehensively review these themes and also highlight important emerging areas of research in this field warranting further investigation, including further illuminating molecular mechanisms of encoding memory, potential and function of transgenerational transmission of innate memory, and the effects of existing therapies on these pathways and the potential of a new class of therapeutics that could coopt them. Sadeghi and Divangahi¹³ describe the evolutionary and phylogenetic origins of trained immunity and the growing catalogue of adaptive features in innate immune cells and their progenitors. Josefowicz and colleagues¹⁴ discuss the potency of HSC reprogramming for changing immune function, including the epigenetic priming of antigen presentation pathways in HSC and new methods that enable analysis of epigenetic reprogramming of immune progenitors in human disease using blood rather than invasive bone marrow biopsies. Neher and colleagues¹⁵ review heterogeneity and plasticity of microglia and provide new analysis of single microglia combined transcriptomic and epigenomic programs, highlighting how these approaches can enhance understanding of pathophysiology involving these important central nervous system myeloid sentinels. Next, Barreiro and colleagues¹⁶ synthesize the fields of population immunogenomics and epigenomics and discuss how a combination of genetic ancestry (and allelic variants) and environment tune diverse immune pathway activities with relevance to our coevolution with global pathogens and natural selection through human history.

Some cytokines play an outsized role in initiating epigenetic inflammatory memory, and a key example of this are interferon (IFN) family cytokines, both type I IFN (IFN-a/b/e/o) and type II IFN (IFN-g). Barrat and colleagues¹⁷ discuss plasmacytoid dendritic cells—potent producers of type I IFN—and present new data on how these cells are regulated and their effects on inflammation and wound healing. Mishra and Ivashkiv¹⁸ highlight the epigenetic regulation of inflammatory genes by IFN signaling, the central activity of STAT1 and IRF1 transcription factors, and present a helpful spectrum of training-priming effects mediated by IFNs. O'Neill and colleagues¹⁹ focus on immunometabolic programs that respond to inflammation and regulate type I IFN production.

Innate immune memory can be encoded beyond immune cells, including in epithelial stem cells,²⁰ and at the tissue level.^{21, 22} How these tissue-level inflammatory memories and adaptations develop and accumulate in early life and what environmental factors influence them is an area of recent and intensive research that may address mechanisms underlying surges in industrial-era diseases. Two reviews cover these concepts with Fernandes and Lim²³ focusing on maternal-immune education in offspring, and Iza and Brown²⁴ discussing early life imprinting of intestinal immune tolerance and the key role of unconventional antigen-presenting cells.

In conclusion, our new and expanding understanding that cellular components of the innate immune system can possess memory will cause us to re-evaluate vaccine strategies that have traditionally targeted T or B cells. Furthermore, because NK cells, ILCs, and myeloid cells can possess anamnestic responses against pathogens, allergens, tumors, and other inflammatory stimuli, new considerations must be taken in how we assess long-lived immune responses following initial exposure to various insults. This is an exciting time in immunology as we seek to more deeply understanding the cellular and molecular mechanisms that underlie generation and maintenance of immunological memory in the context of innate immune system.

数十年的发现使免疫学家将哺乳动物的免疫系统分为两个部分：先天性免疫和适应性免疫。教科书和传统观点将先天性免疫系统描述为快速且非特异性的，而由T细胞和B细胞组成的适应性免疫系统是延迟性的，但具有特异性且具有记忆性。 T 细胞或 B 细胞以外的每一种免疫细胞类型都广泛地归入先天免疫的范畴。然而，最近的研究表明，某些先天免疫细胞可以具有适应性免疫的特征，包括免疫记忆。

先天免疫系统中的记忆（一种独立于 T 细胞和 B 细胞介导的抗原特异性记忆的记忆）的轶事证据已经存在了一个多世纪，包括对植物和动物（包括人类）的观察。然而，直到最近，特定的细胞和分子机制才开始出现，突出了免疫的基本原理和以前未知的调节免疫张力的功能“杠杆”。关键的细胞参与者，自然杀伤 (NK) 细胞和骨髓细胞，处于这场范式转变革命的最前沿，也是本期《免疫学评论》的核心。二十年前，NK 细胞首次被证明具有适应性免疫特征，从抗原特异性到克隆扩增，再到回忆反应的长期记忆。接下来，骨髓细胞被认为在最初的刺激后会产生记忆反应，这一过程被称为“训练免疫”。尽管近年来我们对驱动先天免疫细胞这种适应性特征的机制的理解有所扩大，但关于先天免疫记忆的重要特征仍有很多有待了解。未来的研究将阐明额外的外部信号诱导持久记忆、所需的细胞和代谢过程、潜在的转录因子和表观遗传程序及其持久性，以及最终对健康和疾病的影响。

本卷的第一组综述讨论了小鼠和人类 NK 细胞如何响应各种环境刺激，从而对其克隆性、基因表达、代谢、效应器功能、生存、运输、组织驻留和记忆进行编程。 Delconte 和 Sun ¹以及 Ashkar 及其同事²的评论分别侧重于小鼠和人类 NK 细胞在营养和健康与宿主扰动（包括禁食、感染和癌症）背景下的潜在器官特异性代谢机制。 Aguilar 和 Lanier ³强调了 NK 细胞的适应性特征（包括克隆扩增）如何依赖于包含 ITAM 的受体的特定信号传导。 Degli-Esposti 及其同事、⁴ Hermans 和 O'Sullivan、⁵以及 Ruckert 和 Romagnani ⁶的评论重点关注小鼠和人类 NK 细胞克隆的选择，这些克隆在针对巨细胞病毒感染的反应过程中为效应子功能和生存做好表观遗传学准备，其中随后的记忆 NK 细胞可以驻留在某些组织中，以防止自身免疫和继发感染。

第二组评论围绕先天淋巴细胞（ILC）在暴露于特定炎症信号后如何具有异质性、可塑性和记忆性展开。 Colonna 及其同事⁷回顾了第 1 组 ILC (ILC1) 与 NK 细胞的不同之处，以及如何由共享且独特的转录因子驱动，作为嵌入并驻留在组织中的哨兵。 Martinez-Gonzalez 和 Takei ⁸总结了 2 类 ILC (ILC2) 如何在 2 型细胞因子暴露后介导过敏性回忆反应，以及 ILC2 记忆如何对健康产生有益和有害的影响。 Serafini 和 Di Santo ⁹讨论了第 3 组 ILC (ILC3) 如何在肠道组织中启动以在细菌驱动的炎症期间拥有记忆，以及 ILC3 启动的后果。该组中的所有评论都指出，最近使用各种单细胞测序方法揭示了 ILC1、ILC2 和 ILC3 异质性。

除了缺乏种系重排抗原受体的 NK 细胞和 ILC 之外，先天 T 细胞也被纳入第三组综述中，重点关注粘膜相关不变 T 细胞 (MAIT) 和肿瘤相关先天 T 淋巴细胞。 Prlic 及其同事¹⁰重点关注 MAIT 细胞在健康组织与发炎组织中的功能，并讨论了先天 T 细胞亚群在激活时整合的 TCR 和细胞因子信号。 Li 及其同事¹¹描述了具有细胞毒性潜力的先天 T 细胞子集，它们与传统 T 细胞不同，但类似地被招募到肿瘤中并提供重要的癌症免疫监视功能。

上述这些淋巴谱系先天（和先天样）免疫细胞的一个共同特征是它们具有克隆扩张的共同潜力，如果这些细胞持续存在，特别是在获得性类型特异性炎症程序中，这是一种有效且固有的记忆形成特征。相反，骨髓谱系的细胞通常缺乏广泛扩增的潜力。尽管如此，骨髓细胞具有启动和控制免疫反应的强大能力，因为它们有可能强力启动炎症级联反应、招募多种其他免疫细胞并向 T 细胞和先天淋巴细胞呈递抗原。近年来，已经清楚的是，骨髓细胞中这些强大的免疫启动活动在炎症挑战后会受到持久的表观遗传和代谢调节。这些改变的骨髓表型可以实质性地改变免疫功能，从增强防御到驱动或加剧炎症病理。

该领域的一个表面上的悖论是，许多介导持久先天免疫记忆的骨髓细胞本身是短暂的。本期回顾和阐述的最新研究强调了骨髓祖细胞和自我更新造血干细胞（HSC）作为炎症记忆的主要细胞库的关键作用，能够将表观遗传程序传递给成熟的子代骨髓细胞。 Netea 及其同事¹²全面回顾了这些主题，并强调了该领域值得进一步研究的重要新兴研究领域，包括进一步阐明编码记忆的分子机制、先天记忆跨代传递的潜力和功能，以及现有疗法对这些领域的影响。途径以及可以利用它们的新型疗法的潜力。 Sadeghi 和 Divangahi ¹³描述了经过训练的免疫的进化和系统发育起源，以及先天免疫细胞及其祖细胞中不断增长的适应性特征目录。 Josefowicz 及其同事¹⁴讨论了 HSC 重编程改变免疫功能的效力，包括 HSC 中抗原呈递途径的表观遗传启动，以及能够使用血液而不是侵入性骨髓活检来分析人类疾病中免疫祖细胞表观遗传重编程的新方法。 Neher 及其同事¹⁵回顾了小胶质细胞的异质性和可塑性，并对单个小胶质细胞结合转录组和表观基因组程序进行了新的分析，强调了这些方法如何能够增强对涉及这些重要中枢神经系统骨髓前哨的病理生理学的理解。接下来，Barreiro 及其同事¹⁶综合了群体免疫基因组学和表观基因组学领域，并讨论了遗传祖先（和等位基因变异）和环境的结合如何调整与我们与全球病原体的共同进化和人类历史中的自然选择相关的不同免疫途径活动。

一些细胞因子在启动表观遗传炎症记忆中发挥着巨大作用，其中一个关键例子是干扰素 (IFN) 家族细胞因子，包括 I 型 IFN (IFN-a/b/e/o) 和 II 型 IFN (IFN-g) 。 Barrat 及其同事¹⁷讨论了浆细胞样树突状细胞（I 型 IFN 的有效产生者），并提供了有关这些细胞如何调节及其对炎症和伤口愈合影响的新数据。 Mishra 和 Ivashkiv ¹⁸强调了 IFN 信号传导对炎症基因的表观遗传调控、STAT1 和 IRF1 转录因子的中心活性，并提出了一系列由 IFN 介导的训练启动效应。 O'Neill 及其同事¹⁹专注于对炎症做出反应并调节 I 型干扰素产生的免疫代谢程序。

先天免疫记忆可以在免疫细胞之外进行编码，包括在上皮干细胞中²⁰以及在组织水平。^{21, 22}这些组织水平的炎症记忆和适应如何在生命早期发展和积累，以及哪些环境因素影响它们，是最近深入研究的一个领域，可能会解决工业时代疾病激增的潜在机制。两篇评论涵盖了这些概念，其中 Fernandes 和 Lim ²³重点关注后代的母体免疫教育，Iza 和 Brown ²⁴讨论了肠道免疫耐受的早期生命印记以及非常规抗原呈递细胞的关键作用。

总之，我们对先天免疫系统的细胞成分可以拥有记忆的新认识和不断扩展的认识将使我们重新评估传统上针对 T 或 B 细胞的疫苗策略。此外，由于 NK 细胞、ILC 和骨髓细胞可以对病原体、过敏原、肿瘤和其他炎症刺激物产生记忆反应，因此我们必须重新考虑如何评估初次暴露于各种损伤后的长期免疫反应。这是免疫学领域的一个激动人心的时刻，因为我们寻求更深入地了解先天免疫系统背景下免疫记忆生成和维持的细胞和分子机制。