Immunological Reviews最新文献

The milky spots in omentum are atypical lymphoid tissues that play a pivotal role in regulating immune responses in the peritoneal cavity. The milky spots act as central hubs for collecting antigens and particles from the peritoneal cavity, regulating lymphocyte trafficking, promoting the differentiation and self-renewal of immune cells, and supporting the local germinal centre response. In addition, the milky spots exhibit unique developmental characteristics that combine the features of secondary and tertiary lymphoid tissues. These structures are innately programmed to form during foetal development; however, they can also be formed postnatally in response to peritoneal irritation such as inflammation, infection, obesity, or tumour metastasis. In this review, I discuss emerging perspectives on homeostatic development and organization of the milky spots.

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 pri

Humans exhibit considerable variability in their immune responses to the same immune challenges. Such variation is widespread and affects individual and population-level susceptibility to infectious diseases and immune disorders. Although the factors influencing immune response diversity are partially understood, what mechanisms lead to the wide range of immune traits in healthy individuals remain largely unexplained. Here, we discuss the role that natural selection has played in driving phenotypic differences in immune responses across populations and present-day susceptibility to immune-related disorders. Further, we touch on future directions in the field of immunogenomics, highlighting the value of expanding this work to human populations globally, the utility of modeling the immune response as a dynamic process, and the importance of considering the potential polygenic nature of natural selection. Identifying loci acted upon by evolution may further pinpoint variants critically involved in disease etiology, and designing studies to capture these effects will enrich our understanding of the genetic contributions to immunity and immune dysregulation.

Natural killer (NK) cells are the prototype innate effector lymphocyte population that plays an important role in controlling viral infections and tumors. Studies demonstrating that NK cells form long-lived memory populations, akin to those generated by adaptive immune cells, prompted a revaluation of the potential functions of NK cells. Recent data demonstrating that NK cells are recruited from the circulation into tissues where they form long-lived memory-like populations further emphasize that NK cells have properties that mirror those of adaptive immune cells. NK cells that localize in non-lymphoid tissues are heterogeneous, and there is a growing appreciation that immune responses occurring within tissues are subject to tissue-specific regulation. Here we discuss both the immune effector and immunoregulatory functions of NK cells, with a particular emphasis on the role of NK cells within non-lymphoid tissues and how the tissue microenvironment shapes NK cell-dependent outcomes.

Conventionally, it was thought that innate immunity operated through a simple system of nonspecific responses to an insult. However, this perspective now seems overly simplistic. It has become evident that intricate cooperation and networking among various cells, receptors, signaling pathways, and protein complexes are essential for regulating and defining the overall activation status of the immune response, where the distinction between innate and adaptive immunity becomes ambiguous. Given the evolutionary timeline of vertebrates and the success of plants and invertebrates which depend solely on innate immunity, immune memory cannot be considered an innovation of only the lymphoid lineage. Indeed, the evolutionary innate immune memory program is a conserved mechanism whereby innate immune cells can induce a heightened response to a secondary stimulus due to metabolic and epigenetic reprogramming. Importantly, the longevity of this memory phenotype can be attributed to the reprogramming of self-renewing hematopoietic stem cells (HSCs) in the bone marrow, which is subsequently transmitted to lineage-committed innate immune cells. HSCs reside within a complex regulated network of immune and stromal cells that govern their two primary functions: self-renewal and differentiation. In this review, we delve into the emerging cellular and molecular mechanisms as well as metabolic pathways of innate memory in HSCs, which harbor substantial therapeutic promise.