Innate immunity—With an adaptive twist

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.

SZJ is co-founder of Epistemyx Inc.