Immunological Reviews

The mevalonate pathway is an essential metabolic pathway in T cells regulating development, proliferation, survival, differentiation, and effector functions. The mevalonate pathway is a complex, branched pathway composed of many enzymes that ultimately generate cholesterol and nonsterol isoprenoids. T cells must tightly control metabolic flux through the branches of the mevalonate pathway to ensure sufficient isoprenoids and cholesterol are available to meet cellular demands. Unbalanced metabolite flux through the sterol or the nonsterol isoprenoid branch is metabolically inefficient and can have deleterious consequences for T cell fate and function...

No abstract text is available yet for this article.

Microbes have developed many strategies to subvert host organisms, which, in turn, evolved several innate immune responses. As major lipid storage organelles of eukaryotes, lipid droplets (LDs) are an attractive source of nutrients for invaders. Intracellular viruses, bacteria, and protozoan parasites induce and physically interact with LDs, and the current view is that they "hijack" LDs to draw on substrates for host colonization. This dogma has been challenged by the recent demonstration that LDs are endowed with a protein-mediated antibiotic activity, which is upregulated in response to danger signals and sepsis...

The switch from primitive to definitive hematopoiesis occurs early in development through the emergence of a wave of definitive hematopoietic stem cells from intraembryonic sites, supplanting the original primitive population of extraembryonically derived stem cells. When it became clear that unique features of the fetal immune system could not be reproduced by adult stem cells, it was hypothesized that a lineage of definitive fetal hematopoietic stem cells predominates antenatally, ultimately giving way to an emerging wave of adult stem cells and resulting in a "layered" fetal immune system consisting of overlapping lineages...

Lymphoid cells encompass the adaptive immune system, including T and B cells and Natural killer T cells (NKT), and innate immune cells (ILCs), including Natural Killer (NK) cells. During adult life, these lineages are thought to derive from the differentiation of long-term hematopoietic stem cells (HSCs) residing in the bone marrow. However, during embryogenesis and fetal development, the ontogeny of lymphoid cells is both complex and multifaceted, with a large body of evidence suggesting that lymphoid lineages arise from progenitor cell populations antedating the emergence of HSCs...

It has been over three decades since Drs. Herzenberg and Herzenberg proposed the layered immune system hypothesis, suggesting that different types of stem cells with distinct hematopoietic potential produce specific immune cells. This layering of immune system development is now supported by recent studies showing the presence of fetal-derived immune cells that function in adults. It has been shown that various immune cells arise at different embryonic ages via multiple waves of hematopoiesis from special endothelial cells (ECs), referred to as hemogenic ECs...

Neutrophil recruitment from circulation to sites of inflammation is guided by multiple chemoattractant cues emanating from tissue cells, immune cells, and platelets. Here, we focus on the function of one G-protein coupled receptor, GPR35, in neutrophil recruitment. GPR35 has been challenging to study due the description of multiple ligands and G-protein couplings. Recently, we found that GPR35-expressing hematopoietic cells respond to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). We discuss distinct response profiles of GPR35 to 5-HIAA compared to other ligands...

Leukotriene B4 (LTB4 ) was recognized as an arachidonate-derived chemotactic factor for inflammatory cells and an important drug target even before the molecular identification of its receptors. We cloned the high- and low-affinity LTB4 receptors, BLT1 and BLT2, respectively, and examined their functions by generating and studying gene-targeted mice. BLT1 is involved in the pathogenesis of various inflammatory and immune diseases, including asthma, psoriasis, contact dermatitis, allergic conjunctivitis, age-related macular degeneration, and immune complex-mediated glomerulonephritis...

During embryonic development, several independent generations of hematopoietic cells were identified. They occur in the yolk sac and the intra-embryonic major arteries, in a narrow window of development. They arise sequentially, starting with primitive erythrocytes in the yolk sac blood islands, progressing to less differentiated erythromyeloid progenitors still in the yolk sac, and culminating with multipotent progenitors, some of which will generate the adult hematopoietic stem cell compartment. All these cells contribute to the formation of a layered hematopoietic system that reflects adaptative strategies to the fetal environment and the embryo's needs...

Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid-derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases...

Mast cells (MCs) are evolutionarily ancient innate immune cells with important roles in protective immunity against bacteria, parasites, and venomous animals. They can be found in most organs of the body, where they also contribute to normal tissue functioning, for example by engaging in crosstalk with nerves. Despite this, they are most widely known for their detrimental roles in allergy, anaphylaxis, and atopic disease. Just like macrophages, mast cells were conventionally thought to originate from the bone marrow...

T-cell differentiation is a tightly regulated developmental program governed by interactions between transcription factors (TFs) and chromatin landscapes and affected by signals received from the thymic stroma. This process is marked by a series of checkpoints: T-lineage commitment, T-cell receptor (TCR)β selection, and positive and negative selection. Dynamically changing combinations of TFs drive differentiation along the T-lineage trajectory, through mechanisms that have been most extensively dissected in adult mouse T-lineage cells...

The Innate Lymphoid Cell (ILC) family is a relatively recently described immune cell family involved in innate immune responses and tissue homeostasis. Lymphoid Tissue Inducer (LTi) cells are part of the type 3 (ILC3) family. The ILC3 family is the main ILC population within the embryo, in which the LTi cells are critically associated with embryonic lymph node formation. Recent studies have shown more insights in ILC origin and residency from local embryonic and tissue resident precursors. Embryonic LTi cells originating from a different hemogenic endothelial source were shown to be replaced by HSC derived progenitors in adult...

No abstract text is available yet for this article.

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages...

Historically, the immune system was believed to develop along a linear axis of maturity from fetal life to adulthood. Now, it is clear that distinct layers of immune cells are generated from unique waves of hematopoietic progenitors during different windows of development. This model, known as the layered immune model, has provided a useful framework for understanding why distinct lineages of B cells and γδ T cells arise in succession and display unique functions in adulthood. However, the layered immune model has not been applied to CD8+ T cells, which are still often viewed as a uniform population of cells belonging to the same lineage, with functional differences between cells arising from environmental factors encountered during infection...

The neutrophil phagosome is one of the most hostile environments that bacteria must face and overcome if they are to succeed as pathogens. Targeting bacterial defense mechanisms should lead to new therapies that assist neutrophils to kill pathogens, but this has not yet come to fruition. One of the limiting factors in this effort has been our incomplete knowledge of the complex biochemistry that occurs within the rapidly changing environment of the phagosome. The same compartmentalization that protects host tissue also limits our ability to measure events within the phagosome...

While γδ T cells are present virtually in all vertebrates, there is a remarkable lack of conservation of the TRG and TRD loci underlying the generation of the γδ T cell receptor (TCR), which is associated with the generation of species-specific γδ T cells. A prominent example is the human phosphoantigen-reactive Vγ9Vδ2 T cell subset that is absent in mice. Murine γδ thymocyte cells were among the first immune cells identified to follow a wave-based layered development during embryonic and early life, and since this initial observation, in-depth insight has been obtained in their thymic ontogeny...

The burst of superoxide produced when neutrophils phagocytose bacteria is the defining biochemical feature of these abundant immune cells. But 50 years since this discovery, the vital role superoxide plays in host defense has yet to be defined. Superoxide is neither bactericidal nor is it just a source of hydrogen peroxide. This simple free radical does, however, have remarkable chemical dexterity. Depending on its environment and reaction partners, superoxide can act as an oxidant, a reductant, a nucleophile, or an enzyme substrate...

Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) arise in successive waves during ontogeny, and their properties change significantly throughout life. Ontological changes in HSCs/MPPs underlie corresponding changes in mechanisms of pediatric leukemia initiation. As HSCs and MPPs progress from fetal to neonatal, juvenile and adult stages of life, they undergo transcriptional and epigenetic reprogramming that modifies immune output to meet age-specific pathogenic challenges. Some immune cells arise exclusively from fetal HSCs/MPPs...