Innate lymphoid cells (ILCs) are a family of developmentally related cells that are involved in immunity and in tissue development and remodelling. Recent research has identified several distinct members of this family. Confusingly, many different names have been used to characterize these newly identified ILC subsets. Here, we propose that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.

Innate lymphoid cells--a proposal for uniform nomenclature.

The innate immune system is composed of a diverse array of evolutionarily ancient haematopoietic cell types, including dendritic cells, monocytes, macrophages and granulocytes. These cell populations collaborate with each other, with the adaptive immune system and with non-haematopoietic cells to promote immunity, inflammation and tissue repair. Innate lymphoid cells are the most recently identified constituents of the innate immune system and have been the focus of intense investigation over the past five years. We summarize the studies that formally identified innate lymphoid cells and highlight their emerging roles in controlling tissue homeostasis in the context of infection, chronic inflammation, metabolic disease and cancer.

The biology of innate lymphoid cells

A key feature of the immune system is its ability to induce protective immunity against pathogens while maintaining tolerance towards self and innocuous environmental antigens. Recent evidence suggests that by guiding cells to and within lymphoid organs, CC-chemokine receptor 7 (CCR7) essentially contributes to both immunity and tolerance. This receptor is involved in organizing thymic architecture and function, lymph-node homing of naive and regulatory T cells via high endothelial venules, as well as steady state and inflammation-induced lymph-node-bound migration of dendritic cells via afferent lymphatics. Here, we focus on the cellular and molecular mechanisms that enable CCR7 and its two ligands, CCL19 and CCL21, to balance immunity and tolerance.

CCR7 and its ligands: balancing immunity and tolerance

Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127(+)CD161(+) ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2(+) ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2(+) ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (T(H)2) cytokines.

http://www.dendritics.net/files/documentation/Mjosberg_JM_et_al,_2011,_R34-34.pdf

Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.

The maintenance of barrier function at exposed surfaces of the mammalian body is essential for limiting exposure to environmental stimuli, preventing systemic dissemination of commensal and pathogenic microbes and retaining normal homeostasis of the entire body. Indeed, dysregulated barrier function is associated with many infectious and inflammatory diseases, including psoriasis, influenza, inflammatory bowel disease and human immunodeficiency virus, which collectively afflict millions of people worldwide. Studies have shown that interleukin 22 (IL-22) is expressed at barrier surfaces and that its expression is dysregulated in certain human diseases, which suggests a critical role in the maintenance of normal barrier homeostasis. Consistent with that, studies of mouse model systems have identified a critical role for signaling by IL-22 through its receptor (IL-22R) in the promotion of antimicrobial immunity, inflammation and tissue repair at barrier surfaces. In this review we will discuss how the expression of IL-22 and IL-22R is regulated, the functions of the IL-22-IL-22R pathway in regulating immunity, inflammation and tissue homeostasis, and the therapeutic potential of targeting this pathway in human disease.

Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22

The generation of lymphoid microenvironments in early life depends on the interaction of lymphoid tissue-inducer cells with stromal lymphoid tissue-organizer cells. Whether this cellular interface stays operational in adult secondary lymphoid organs has remained elusive. We show here that during acute infection with lymphocytic choriomeningitis virus, antiviral cytotoxic T cells destroyed infected T cell zone stromal cells, which led to profound disruption of secondary lymphoid organ integrity. Furthermore, the ability of the host to respond to secondary antigens was lost. Restoration of the lymphoid microanatomy was dependent on the proliferative accumulation of lymphoid tissue-inducer cells in secondary lymphoid organs during the acute phase of infection and lymphotoxin alpha(1)beta(2) signaling. Thus, crosstalk between lymphoid tissue-inducer cells and stromal cells is reactivated in adults to maintain secondary lymphoid organ integrity and thereby contributes to the preservation of immunocompetence.

Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone.

This study provides a detailed spatiotemporal interaction analysis between B cells, Th cells, and dendritic cells (DC) during the generation of protective antiviral B cell immunity. Following vesicular stomatitis virus (VSV) infection, conditional ablation of CD11c-positive DC at the time-point of infection did not impair extrafollicular plasma cell generation and Ig class switching. In contrast, the generation of Th and B cell responses following immunization with recombinant VSV-glycoprotein was DC-dependent. Furthermore, we show that the CCR7-dependent interplay of the three cell-types is crucial for virus-neutralizing B cell responses in the presence of limiting amounts of Ag. An immediate event following VSV infection was the CCR7-mediated interaction of VSV-specific B and Th cells at the T cell-B cell zone border that facilitated plasma cell differentiation and Th cell activation. Taken together, these experiments provide evidence for a direct, CCR7-orchestrated and largely DC-independent mutual activation of Th cells and Ag-specific B cells that is most likely a critical step during early immune responses against cytopathic viruses.

/pdf/dendritic-cell-independent-b-cell-activation-during-acute-8907vi1we4.pdf

Dendritic Cell-Independent B Cell Activation During Acute Virus Infection: A Role for Early CCR7-Driven B-T Helper Cell Collaboration

Modified nucleoside triphosphates (NTPs) are powerful probes and medicines, but their anionic character impedes membrane permeability. As such, invasive delivery techniques, transport carriers, or prodrug strategies are required for their in vivo use. Here, we present a fluorescent 2'-deoxyribonucleoside triphosphate "TAMRA-dATP" that exhibits surprisingly high bioavailability in vivo. TAMRA-dATP spontaneously forms nanoparticles in Mg+2-containing buffers that are taken into the vesicles of living cells and animals by energy-dependent processes. In cell cultures, photochemical activation with yellow laser light (561 nm) facilitated endosomal escape of TAMRA-dATP, resulting in its metabolic incorporation into DNA in vitro. In contrast, in vivo studies revealed that TAMRA-dATP is extensively trafficked by active pathways into cellular DNA of zebrafish (Danio rerio) and Caenorhabditis elegans where DNA labeling was observed in live animals, even without photochemical release. Metabolic labeling of DNA in whole, living animals can therefore be achieved by simply soaking animals in a buffer containing TAMRA-dATP or a structurally related compound, Cy3-dATP.

Active Uptake and Trafficking of Nucleoside Triphosphates In Vivo.

Simple Summary Melanoma is produced by the malignant transformation of the pigmented cells in the skin. It is the deadliest form of skin cancer and a global medical burden. Recent research suggests that extracellular vesicles improve diagnosis and treatment of melanoma. Extracellular vesicles are virus-like vehicles that are released into the blood and other body fluids by most cell types, including cancer cells. They sequester molecular substances from the cytoplasm and transport them as messengers to target cells. Thanks to these properties, extracellular vesicles provide a molecular fingerprint of the cell of origin and can serve as biomarkers for cancer diagnosis or prognosis. In addition, molecular signals exchanged through extracellular vesicles between cancer cells and the tumor environment can reveal signaling pathways that are important for cancer progression. In this review we give a general overview of extracellular vesicles and focus on their impact on melanoma progression and potential use as biomarkers for monitoring and treating melanoma. Abstract Cutaneous melanoma arises from a malignant transformation of the melanocytes in the skin. It is the deadliest form of skin cancer owing to its potential to metastasize. While recent advances in immuno-oncology have been successful in melanoma treatment, not all the patients respond to the treatment equally, thus individual pre-screening and personalized combination therapies are essential to stratify and monitor patients. Extracellular vesicles (EVs) have emerged as promising biomarker candidates to tackle these challenges. EVs are ~50–1000-nm-sized, lipid bilayer-enclosed spheres, which are secreted by almost all cell types, including cancer cells. Their cargo, such as nucleic acids, proteins, lipids, amino acids, and metabolites, can be transferred to target cells. Thanks to these properties, EVs can both provide a multiplexed molecular fingerprint of the cell of origin and thus serve as potential biomarkers, or reveal pathways important for cancer progression that can be targeted pharmaceutically. In this review we give a general overview of EVs and focus on their impact on melanoma progression. In particular, we shed light on the role of EVs in shaping the tumor–stroma interactions that facilitate metastasis and summarize the latest findings on molecular profiling of EV-derived miRNAs and proteins that can serve as potential biomarkers for melanoma progression.

https://www.mdpi.com/2072-6694/14/13/3086/pdf?version=1655981156

The Role of Extracellular Vesicles in Melanoma Progression

Cell invasion is an initiating event during tumor cell metastasis and an essential process during development. A screen of C. elegans orthologs of genes overexpressed in invasive human melanoma cells has identified several components of the conserved DNA pre-replication complex (pre-RC) as positive regulators of anchor cell (AC) invasion. The pre-RC genes function cell-autonomously in the G1-arrested AC to promote invasion, independently of their role in licensing DNA replication origins in proliferating cells. While the helicase activity of the pre-RC is necessary for AC invasion, the downstream acting DNA replication initiation factors are not required. The pre-RC promotes the invasive fate by regulating the expression of extracellular matrix genes and components of the PI3K signaling pathway. Increasing PI3K pathway activity partially suppressed the AC invasion defects caused by pre-RC depletion, suggesting that the PI3K pathway is one critical pre-RC target. We propose that the pre-RC, or a part of it, acts in the postmitotic AC as a transcriptional regulator that facilitates the switch to an invasive phenotype.

/pdf/a-dna-replication-independent-function-of-pre-replication-1xoo5zo1.pdf

Evelyn Lattmann

Papers

Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone.

Dendritic Cell-Independent B Cell Activation During Acute Virus Infection: A Role for Early CCR7-Driven B-T Helper Cell Collaboration

Active Uptake and Trafficking of Nucleoside Triphosphates In Vivo.

The Role of Extracellular Vesicles in Melanoma Progression

A DNA replication-independent function of pre-replication complex genes during cell invasion in C. elegans