Emerging concepts and future challenges in innate lymphoid cell biology

Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role.

Download Full-text

A novel innate lymphoid cell delineates childhood autoimmune arthritis

10.1101/416784 ◽

2018 ◽

Author(s):

Martin Del Castillo Velasco-Herrera ◽

Matthew D Young ◽

Felipe A Vieira Braga ◽

Elizabeth C. Rosser ◽

Elena Miranda ◽

...

Keyword(s):

Autoimmune Disease ◽

Synovial Fluid ◽

Immune Cells ◽

Messenger Rna ◽

Cell Types ◽

Lymphoid Cells ◽

Autoimmune Arthritis ◽

Cellular Interactions ◽

Activated T Cells ◽

Adaptive Immune Cells

Inflammation in autoimmune disease is mediated by a complex network of interacting cells. Their identity and cross-talk are encoded in messenger RNA (mRNA). Juvenile idiopathic arthritis (JIA), a chronic autoimmune arthritis of childhood, is characterised by synovial inflammation with infiltration of both innate and adaptive immune cells1. Activated T cells play a role in disease2 but the cell types that drive the recruitment and activation of immune cells within the synovium are not known. Here, we utilised droplet-based and full length single cell mRNA sequencing to obtain a quantitative map of the cellular landscape of JIA. We studied 45,715 cells from the synovial fluid of inflamed knee joints and peripheral blood. We identified a population of synovial innate lymphoid cells (ILCs), shared across patients, that exhibited a unique transcriptional profile in comparison to canonical ILC subtypes. Validation at protein-level across a spectrum of autoimmune arthritides revealed that these ILCs are pathologically expanded in a particular type of JIA. Using statistical tools to assess cellular interactions in synovial fluid, ILCs emerged as a central node of communication, expressing the full repertoire of genes required to orchestrate and maintain the inflammatory milieu. Several ILC-mediated signalling pathways may lend themselves as novel therapeutic targets. Together our findings demonstrate a distinct ILC subtype associated with a tissue-specific childhood autoimmune disease.

Download Full-text

Cell biology of fat storage

Molecular Biology of the Cell ◽

10.1091/mbc.e15-10-0749 ◽

2016 ◽

Vol 27 (16) ◽

pp. 2523-2527 ◽

Cited By ~ 63

Author(s):

Paul Cohen ◽

Bruce M. Spiegelman

Keyword(s):

Immune Cells ◽

Cell Biology ◽

Critical Role ◽

Cell Types ◽

Fat Cells ◽

Obesity And Diabetes ◽

Beige Adipocytes ◽

Therapeutic Development ◽

White Fat

The worldwide epidemic of obesity and type 2 diabetes has greatly increased interest in the biology and physiology of adipose tissues. Adipose (fat) cells are specialized for the storage of energy in the form of triglycerides, but research in the last few decades has shown that fat cells also play a critical role in sensing and responding to changes in systemic energy balance. White fat cells secrete important hormone-like molecules such as leptin, adiponectin, and adipsin to influence processes such as food intake, insulin sensitivity, and insulin secretion. Brown fat, on the other hand, dissipates chemical energy in the form of heat, thereby defending against hypothermia, obesity, and diabetes. It is now appreciated that there are two distinct types of thermogenic fat cells, termed brown and beige adipocytes. In addition to these distinct properties of fat cells, adipocytes exist within adipose tissue, where they are in dynamic communication with immune cells and closely influenced by innervation and blood supply. This review is intended to serve as an introduction to adipose cell biology and to familiarize the reader with how these cell types play a role in metabolic disease and, perhaps, as targets for therapeutic development.

Download Full-text

T-cells play the classics with a different spin

Molecular Biology of the Cell ◽

10.1091/mbc.e13-11-0636 ◽

2014 ◽

Vol 25 (11) ◽

pp. 1699-1703 ◽

Cited By ~ 4

Author(s):

Michael L. Dustin

Keyword(s):

T Cells ◽

Plasma Membrane ◽

Immune Cells ◽

Cell Biology ◽

Immunological Synapse ◽

Cell Communication ◽

Intraflagellar Transport ◽

Cell Types ◽

Immune Synapse ◽

And Function

The immune system uses much of the classic machinery of cell biology, but in ways that put a different spin on organization and function. Striking recent examples include the demonstration of intraflagellar transport protein and hedgehog contributions to the immune synapse, even though immune cells lack a primary cilium that would be the typical setting for this machinery. In a second example, lymphocytes have their own subfamily of integrins, the β2 subfamily, and only integrins in this family form a stable adhesion ring using freely mobile ligands, a key feature of the immunological synapse. Finally, we showed recently that T-cells use endosomal sorting complexes required for transport (ESCRTs) at the plasma membrane to generate T-cell antigen receptor–enriched microvesicles. It is unusual for the ESCRT pathway to operate at the plasma membrane, but this may allow a novel form of cell–cell communication by providing a multivalent ligand for major histocompatibility complex–peptide complexes and perhaps other receptors on the partnering B-cell. Immune cells are thus an exciting system for novel cell biology even with classical pathways that have been studied extensively in other cell types.

Download Full-text

An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation

Circulation Research ◽

10.1161/circresaha.120.315900 ◽

2020 ◽

Vol 126 (11) ◽

pp. 1565-1589 ◽

Cited By ~ 5

Author(s):

Lakshmi Arivazhagan ◽

Henry H. Ruiz ◽

Robin A. Wilson ◽

Michaele B. Manigrasso ◽

Paul F. Gugger ◽

...

Keyword(s):

Physical Activity ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Innate Immune ◽

Lymphoid Cells ◽

Innate Immune Cells ◽

Metabolic Perturbation ◽

Adaptive Immune Cells ◽

Reduced Physical Activity

The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow–derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type–specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.

Download Full-text

Biology and pathology of the uterine microenvironment and its natural killer cells

Cellular and Molecular Immunology ◽

10.1038/s41423-021-00739-z ◽

2021 ◽

Author(s):

Fuyan Wang ◽

Anita Ellen Qualls ◽

Laia Marques-Fernandez ◽

Francesco Colucci

Keyword(s):

Natural Killer ◽

Fetal Growth ◽

Immune Cells ◽

Smooth Muscle Actin ◽

Lymphoid Cells ◽

Unk Cells ◽

New Frontier ◽

Uterine Mucosa ◽

Blastocyst Implantation ◽

And Function

AbstractTissues are the new frontier of discoveries in immunology. Cells of the immune system are an integral part of tissue physiology and immunity. Determining how immune cells inhabit, housekeep, and defend gut, lung, brain, liver, uterus, and other organs helps revealing the intimate details of tissue physiology and may offer new therapeutic targets to treat pathologies. The uterine microenvironment modulates the development and function of innate lymphoid cells [ILC, largely represented by natural killer (NK) cells], macrophages, T cells, and dendritic cells. These immune cells, in turn, contribute to tissue homeostasis. Regulated by ovarian hormones, the human uterine mucosa (endometrium) undergoes ~400 monthly cycles of breakdown and regeneration from menarche to menopause, with its fibroblasts, glands, blood vessels, and immune cells remodeling the tissue into the transient decidua. Even more transformative changes occur upon blastocyst implantation. Before the placenta is formed, the endometrial glands feed the embryo by histiotrophic nutrition while the uterine spiral arteries are stripped of their endothelial layer and smooth muscle actin. This arterial remodeling is carried out by invading fetal trophoblast and maternal immune cells, chiefly uterine NK (uNK) cells, which also assist fetal growth. The transformed arteries no longer respond to maternal stimuli and meet the increasing demands of the growing fetus. This review focuses on how the everchanging uterine microenvironment affects uNK cells and how uNK cells regulate homeostasis of the decidua, placenta development, and fetal growth. Determining these pathways will help understand the causes of major pregnancy complications.

Download Full-text

Single cell analysis reveals immune cell–adipocyte crosstalk regulating the transcription of thermogenic adipocytes

eLife ◽

10.7554/elife.49501 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 17

Author(s):

Prashant Rajbhandari ◽

Douglas Arneson ◽

Sydney K Hart ◽

In Sook Ahn ◽

Graciel Diamante ◽

...

Keyword(s):

Single Cell ◽

Immune Cells ◽

Immune Cell ◽

Single Cell Analysis ◽

Metabolic Response ◽

Cell Types ◽

Specific Cell ◽

Beneficial Effects ◽

Thermogenic Adipocytes ◽

And Function

Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor α in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. Single Nuclei Adipocyte RNA-sequencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Rα deletion. Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function.

Download Full-text

Form and Function in Cells of the Brain

The Neuron ◽

10.1093/med/9780199773893.003.0002 ◽

2015 ◽

pp. 23-38

Author(s):

Irwin B. Levitan ◽

Leonard K. Kaczmarek

Keyword(s):

Axonal Transport ◽

Molecular Motors ◽

Critical Role ◽

Neuronal Cell ◽

Cell Types ◽

Neuronal Cell Body ◽

Long Distance ◽

Form And Function ◽

And Function ◽

The Brain

This chapter examines unique mechanisms that the neuron has evolved to establish and maintain the form required for its specialized signaling functions. Unlike some other organs, the brain contains a variety of cell types including several classes of glial cells, which play a critical role in the formation of the myelin sheath around axons and may be involved in immune responses, synaptic transmission, and long-distance calcium signaling in the brain. Neurons share many features in common with other cells (including glia), but they are distinguished by their highly asymmetrical shapes. The neuronal cytoskeleton is essential for establishing this cell shape during development and for maintaining it in adulthood. The process of axonal transport moves vesicles and other organelles to regions remote from the neuronal cell body. Proteins such as kinesin and dynein, called molecular motors, make use of the energy released by hydrolysis of ATP to drive axonal transport.

Download Full-text

The immunoregulation of mesenchymal stem cells plays a critical role in improving the prognosis of liver transplantation

Journal of Translational Medicine ◽

10.1186/s12967-019-02167-0 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 5

Author(s):

Chenxia Hu ◽

Lanjuan Li

Keyword(s):

Liver Transplantation ◽

Natural Killer ◽

Immune Cells ◽

Adaptive Systems ◽

Critical Role ◽

Arterial System ◽

Cell Mediated Immunity ◽

Adaptive Immune Cells

AbstractThe liver is supplied by a dual blood supply, including the portal venous system and the hepatic arterial system; thus, the liver organ is exposed to multiple gut microbial products, metabolic products, and toxins; is sensitive to extraneous pathogens; and can develop liver failure, liver cirrhosis and hepatocellular carcinoma (HCC) after short-term or long-term injury. Although liver transplantation (LT) serves as the only effective treatment for patients with end-stage liver diseases, it is not very popular because of the complications and low survival rates. Although the liver is generally termed an immune and tolerogenic organ with adaptive systems consisting of humoral immunity and cell-mediated immunity, a high rejection rate is still the main complication in patients with LT. Growing evidence has shown that mesenchymal stromal cell (MSC) transplantation could serve as an effective immunomodulatory strategy to induce tolerance in various immune-related disorders. MSCs are reported to inhibit the immune response from innate immune cells, including macrophages, dendritic cells (DCs), natural killer cells (NK cells), and natural killer T (NKT) cells, and that from adaptive immune cells, including T cells, B cells and other liver-specific immune cells, for the generation of a tolerogenic microenvironment. In this review, we summarized the relationship between LT and immunoregulation, and we focused on how to improve the effects of MSC transplantation to improve the prognosis of LT. Only after exhaustive clarification of the potential immunoregulatory mechanisms of MSCs in vitro and in vivo can we implement MSC protocols in routine clinical practice to improve LT outcome.

Download Full-text

Long Noncoding RNA in Myeloid and Lymphoid Cell Differentiation, Polarization and Function

Cells ◽

10.3390/cells9020269 ◽

2020 ◽

Vol 9 (2) ◽

pp. 269 ◽

Cited By ~ 5

Author(s):

Imran Ahmad ◽

Araceli Valverde ◽

Fayek Ahmad ◽

Afsar Raza Naqvi

Keyword(s):

Cell Differentiation ◽

Immune Cells ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Immune Cell ◽

Lymphoid Cells ◽

Tissue Cell ◽

Specific Expression ◽

And Function

Long noncoding RNA (lncRNA) are a class of endogenous, non-protein coding RNAs that are increasingly being associated with various cellular functions and diseases. Yet, despite their ubiquity and abundance, only a minute fraction of these molecules has an assigned function. LncRNAs show tissue-, cell-, and developmental stage-specific expression, and are differentially expressed under physiological or pathological conditions. The role of lncRNAs in the lineage commitment of immune cells and shaping immune responses is becoming evident. Myeloid cells and lymphoid cells are two major classes of immune systems that work in concert to initiate and amplify innate and adaptive immunity in vertebrates. In this review, we provide mechanistic roles of lncRNA through which these noncoding RNAs can directly participate in the differentiation, polarization, and activation of myeloid (monocyte, macrophage, and dendritic cells) and lymphoid cells (T cells, B cells, and NK cells). While our knowledge on the role of lncRNA in immune cell differentiation and function has improved in the past decade, further studies are required to unravel the biological role of lncRNAs and identify novel mechanisms of lncRNA functions in immune cells. Harnessing the regulatory potential of lncRNAs can provide novel diagnostic and therapeutic targets in treating immune cell related diseases.

Download Full-text

Hypoxia. 4. Hypoxia and ion channel function

AJP Cell Physiology ◽

10.1152/ajpcell.00512.2010 ◽

2011 ◽

Vol 300 (5) ◽

pp. C951-C967 ◽

Cited By ~ 57

Author(s):

Larissa A. Shimoda ◽

Jan Polak

Keyword(s):

Ion Channels ◽

Cell Function ◽

Critical Role ◽

Cardiac Contractility ◽

Cell Types ◽

Cellular Processes ◽

Oxygen Sensitive ◽

Sense And Respond ◽

And Function ◽

And Control

The ability to sense and respond to oxygen deprivation is required for survival; thus, understanding the mechanisms by which changes in oxygen are linked to cell viability and function is of great importance. Ion channels play a critical role in regulating cell function in a wide variety of biological processes, including neuronal transmission, control of ventilation, cardiac contractility, and control of vasomotor tone. Since the 1988 discovery of oxygen-sensitive potassium channels in chemoreceptors, the effect of hypoxia on an assortment of ion channels has been studied in an array of cell types. In this review, we describe the effects of both acute and sustained hypoxia (continuous and intermittent) on mammalian ion channels in several tissues, the mode of action, and their contribution to diverse cellular processes.

Download Full-text