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Key Points Constitutively migrating LY6C + monocytes can retain their own properties without differentiating into a bone fide macrophage or dendritic cell. Monocytes can replenish tissue-specific macrophages if a residential macrophage niche opens. Monocytes are as abundant as dendritic cell subsets in human and mouse lymph nodes in the steady state, and they are more abundant during inflammation. Monocytes are antigen-presenting cells that load antigen on MHC class I and II molecules and prime CD8 + and CD4 + T cells. Monocytes have both pro-inflammatory and anti-inflammatory properties. Monocytes show plasticity and can differentiate into many different cell types in a manner that is dictated by the tissue environment. Monocytes not only serve as precursors for macrophages, but also contribute to tissue immunity by presenting antigen to T cells and producing immunomodulatory mediators. In this Review, the authors discuss some of these less well-appreciated immune functions of monocytes. Monocytes develop in the bone marrow and represent the primary type of mononuclear phagocyte found in the blood. They were long thought of as a source for tissue macrophages, but recent studies indicate more complex roles for monocytes, both within the circulation and after their migration into tissues and lymphoid organs. In this Review, we discuss the newer concepts underlying the maturation of emigrating monocytes into different classes of tissue macrophages, as well as their potential functions, as monocyte-derived cells, in the tissues. In addition, we consider the emerging roles for monocytes in adaptive immunity as antigen-presenting cells.

Single-cell technologies have enabled extensive profiling studies of human and mouse tissues and the identification of an ever-growing number of transcriptional clusters within the dendritic cell (DC) lineage. Here, we discuss the importance of differentiating cell subsets from cell states when annotating DC clusters and propose a revised nomenclature of the DC lineage that integrates experimentally validated knowledge and unbiased transcriptomic profiling results.In this Comment article, Florent Ginhoux, Martin Guilliams and Miriam Merad call for a revised nomenclature of the dendritic cell (DC) lineage to distinguish between DC subsets and DC states and resolve confusion in the light of single-cell transcriptional profiling results.

Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8 + T cells. cDC1 cells can be identified in mice and humans by high expression of DNGR-1 (also known as CLEC9A), a receptor that binds dead-cell debris and facilitates XP of corpse-associated antigens. Here, we show that DNGR-1 is a dedicated XP receptor that signals upon ligand engagement to promote phagosomal rupture. This allows escape of phagosomal contents into the cytosol, where they access the endogenous major histocompatibility complex class I antigen processing pathway. The activity of DNGR-1 maps to its signaling domain, which activates SYK and NADPH oxidase to cause phagosomal damage even when spliced into a heterologous receptor and expressed in heterologous cells. Our data reveal the existence of innate immune receptors that couple ligand binding to endocytic vesicle damage to permit MHC class I antigen presentation of exogenous antigens and to regulate adaptive immunity. The mechanism by which ingested material accesses the cytosol for cross-presentation is unclear. Caetano Reis e Sousa and colleagues demonstrate that signaling via the lectin receptor DNGR-1 ruptures the phagosome and releases its contents to the cytosol for cross-presentation.

Key Points The cell fate decisions of developing thymocytes are coordinated by interactions with self-peptide–MHC complexes that are displayed by various types of thymic antigen presenting cells (APCs). Different thymic APCs use cell type-specific strategies of self antigen sampling and processing. Cortical thymic epithelial cells (cTECs) use unique proteolytic pathways to generate MHC class I-bound and MHC class II-bound peptides, and these 'private' peptides expressed by cTECs are critical for the positive selection of a fully functional T cell repertoire. Several types of haematopoieteic and non-haematopoietic APCs cooperatively present self antigens for central tolerance induction. Medullary thymic epithelial cells (mTECs) promiscuously express peripheral self antigens and autonomously present these to thymocytes. Different subsets of dendritic cells sample blood-borne and mTEC-derived self antigens within the thymus or transport peripheral self antigens into the thymus. Here, the authors describe the key characteristics of the different antigen-presenting cell (APC) populations that govern T cell development in the thymus. They discuss how the interactions that occur between thymocytes and thymic APCs shape the mature T cell repertoire, and how they subsequently affect the nature of peripheral immune responses. The fate of developing T cells is specified by the interaction of their antigen receptors with self-peptide–MHC complexes that are displayed by thymic antigen-presenting cells (APCs). Various subsets of thymic APCs are strategically positioned in particular thymic microenvironments and they coordinate the selection of a functional and self-tolerant T cell repertoire. In this Review, we discuss the different strategies that these APCs use to sample and process self antigens and to thereby generate partly unique, 'idiosyncratic' peptide–MHC ligandomes. We discuss how the particular composition of the peptide–MHC ligandomes that are presented by specific APC subsets not only shapes the T cell repertoire in the thymus but may also indelibly imprint the behaviour of mature T cells in the periphery.

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment 1 , 2 . The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn’s disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (T reg ) and T follicular helper (T FH ) cells under homeostatic conditions, but induce inflammatory T helper 17 (T H 17) cells when induced T reg (iT reg ) cells are compromised 3 , 4 . How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iT reg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of T reg cells. These RORγt + cells—probably type 3 innate lymphoid cells and/or Janus cells 5 —require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator α v integrin. In the absence of any of these factors, there was expansion of pathogenic T H 17 cells instead of iT reg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions. Induction of T regulatory cells by gut microbes is mediated by antigen-presenting RORγt + cells, unlike that of T follicular helper and T helper 17 cells, which requires different cell types.

Key Points Extracellular vesicles, including exosomes, are small membrane vesicles that are derived from multivesicular bodies or that bud from the plasma membrane. Most, if not all, cell types release extracellular vesicles that then enter almost all bodily fluids. Extracellular vesicles, which carry proteins, lipids, mRNAs and non-coding RNAs including microRNAs, have important roles in intercellular communication, both locally and systemically, by transferring their contents between cells. Extracellular vesicles are involved in numerous physiological processes, and vesicles from both non-immune cells, such as stem cells, and immune cells participate in immune regulation. As a result of the immunoregulatory activity of extracellular vesicles, therapeutic approaches using these vesicles are being developed and clinically tested for the treatment of inflammatory and autoimmune diseases and cancer. Extracellular vesicles that carry tumour or pathogenic peptides presented by MHC class I and MHC class II complexes can stimulate CD4 + and CD8 + T cells directly as well as indirectly through an interaction with antigen-presenting cells (APCs). Peptide–MHC complexes of extracellular vesicles that become attached or fused to APC surfaces might also be directly presented to T cells without the need for peptide–MHC complex reprocessing through a mechanism known as cross-dressing. Extracellular vesicles can be immunostimulatory through the transfer of both antigens and signals to APCs to promote their activation into immunogenic APCs. By contrast, certain extracellular vesicles can render APCs immunosuppressive through multiple mechanisms, which results in the induction of regulatory T cells. The immunoregulatory activity of tumour-derived and APC-derived extracellular vesicles can be enhanced by treatment of the parental cells with cytokines, by stress (such as heat shock) or by gene transfer of immunoregulatory factors such as CD95 ligand, indoleamine 2,3-dioxygenase or interleukin-4. Extracellular vesicles, including exosomes, provide a means of intercellular communication for immune regulation. Here, the authors describe how the proteins, nucleic acids and other molecules that they carry influence immune responses, and explore their potential use in the treatment of inflammatory and autoimmune diseases, and cancer. Extracellular vesicles, including exosomes, are small membrane vesicles derived from multivesicular bodies or from the plasma membrane. Most, if not all, cell types release extracellular vesicles, which then enter the bodily fluids. These vesicles contain a subset of proteins, lipids and nucleic acids that are derived from the parent cell. It is thought that extracellular vesicles have important roles in intercellular communication, both locally and systemically, as they transfer their contents, including proteins, lipids and RNAs, between cells. Extracellular vesicles are involved in numerous physiological processes, and vesicles from both non-immune and immune cells have important roles in immune regulation. Moreover, extracellular vesicle-based therapeutics are being developed and clinically tested for the treatment of inflammatory diseases, autoimmune disorders and cancer. Given the tremendous therapeutic potential of extracellular vesicles, this Review focuses on their role in modulating immune responses, as well as their potential therapeutic applications.

Key Points MHC class II molecules bind antigenic peptides that are generated in endosomal–lysosomal antigen-processing compartments. These peptides are derived from proteins that access these compartments using various endocytic pathways and also as a result of autophagy. Proteolysis in antigen-processing compartments is regulated in antigen-presenting cells (APCs) to favour the formation of antigenic peptides that can bind to MHC class II and to avoid the complete hydrolysis of proteins to very short peptides or to amino acids. Nonspecific endocytosis processes are terminated following dendritic cell (DC) activation, but mature DCs can still internalize antigen by receptor-mediated endocytosis or phagocytosis. Using these pathways, mature DCs can generate peptide–MHC class II complexes and activate naive CD4 + T cells. The formation of antigen-processing compartments is regulated during APC activation. B cell activation results in MHC class II recruitment to endosomes and lysosomes to form these compartments, whereas in DCs, lysosomal proteases relocalize to antigen-processing compartments and enhance antigen proteolysis. APC activation leads to efficient generation of peptide–MHC class II complexes and markedly increases the expression of these complexes on the APC plasma membrane. Increased surface expression of peptide–MHC class II complexes on activated APCs is a result of enhanced MHC class II transcription and/or translation, movement of intracellular peptide–MHC class II complexes to the APC plasma membrane and reduced lysosomal MHC class II degradation. Expression of the E3 ubiquitin ligase MARCH1 by immature APCs promotes rapid turnover of peptide–MHC class II complexes. DC activation terminates MARCH1 expression and ubiquitylation of peptide–MHC class II complexes, thus increasing the half-life of peptide–MHC class II complexes. To play their part in the generation of effective adaptive immune responses, different types of antigen-presenting cell (APC) take up and process antigen in different ways. The length of time that peptide–MHC class II complexes are present on APC surfaces can also vary depending on the cell type. This Review describes the different modes and mechanisms that regulate MHC class II processing and presentation. Antigenic peptide-loaded MHC class II molecules (peptide–MHC class II) are constitutively expressed on the surface of professional antigen-presenting cells (APCs), including dendritic cells, B cells, macrophages and thymic epithelial cells, and are presented to antigen-specific CD4 + T cells. The mechanisms of antigen uptake, the nature of the antigen processing compartments and the lifetime of cell surface peptide–MHC class II complexes can vary depending on the type of APC. It is likely that these differences are important for the function of each distinct APC subset in the generation of effective adaptive immune responses. In this Review, we describe our current knowledge of the mechanisms of uptake and processing of antigens, the intracellular formation of peptide–MHC class II complexes, the intracellular trafficking of peptide–MHC class II complexes to the APC plasma membrane and their ultimate degradation.

Plasmacytoid dendritic cells (pDCs) are an immune subset devoted to the production of high amounts of type 1 interferons in response to viral infections. Whereas conventional dendritic cells (cDCs) originate mostly from a common dendritic cell progenitor (CDP), pDCs have been shown to develop from both CDPs and common lymphoid progenitors. Here, we found that pDCs developed predominantly from IL-7R + lymphoid progenitor cells. Expression of SiglecH and Ly6D defined pDC lineage commitment along the lymphoid branch. Transcriptional characterization of SiglecH + Ly6D + precursors indicated that pDC development requires high expression of the transcription factor IRF8, whereas pDC identity relies on TCF4. RNA sequencing of IL-7R + lymphoid and CDP-derived pDCs mirrored the heterogeneity of mature pDCs observed in single-cell analysis. Both mature pDC subsets are able to secrete type 1 interferons, but only myeloid-derived pDCs share with cDCs their ability to process and present antigen. Tussiwand and colleagues show that pDCs develop predominantly from IL-7R + lymphoid progenitor cells and that mature pDCs are transcriptionally and functionally heterogenous, on the basis of their lymphoid or myeloid lineage.

Key Points Expression levels of the activating Fc receptors for IgG (FcγRs) are much higher on monocyte-derived dendritic cells (moDCs) and macrophages than on conventional DCs (cDCs) and plasmacytoid DCs (pDCs), and can be used to separate these cells in mice and humans. The inhibitory FcγR is broadly expressed on all antigen-presenting cells (APCs). The uptake of antigens via distinct extracellular and intracellular FcγRs influences antigen presentation, and determines whether the antigen is degraded or presented and the type of epitopes that are presented. Most FcγRs induce the expression of activating signals in APCs that can influence APC activation, the ability of APCs to kill pathogens and the APC-mediated regulation of T cell responses. Through concomitant expression of the inhibitory FcγR, the immune system can set strict activation thresholds in particular APCs. The main function of activating FcγRs on moDCs is to modify the encounters of moDCs with T cells at sites of inflammation, whereas the function of FcγRs on macrophages is to promote the clearance of pathogens in the periphery. The role of FcγRs on cDCs and pDCs deserves more attention as there is a striking lack of studies that address the role of FcγRs on these cells in vivo . The main function of the inhibitory FcγR on these cells might be the induction of tolerance. Here, the authors review the expression patterns and function of Fc receptors for IgG (FcγRs) on conventional dendritic cells (DCs), monocyte-derived DCs, plasmacytoid DCs and macrophages in the steady state and at sites of inflammation. They also discuss emerging concepts and areas that require further investigation. Dendritic cells (DCs) and macrophages use various receptors to recognize foreign antigens and to receive feedback control from adaptive immune cells. Although it was long believed that all immunoglobulin Fc receptors are universally expressed by phagocytes, recent findings indicate that only monocyte-derived DCs and macrophages express high levels of activating Fc receptors for IgG (FcγRs), whereas conventional and plasmacytoid DCs express the inhibitory FcγR. In this Review, we discuss how the uptake, processing and presentation of antigens by DCs and macrophages is influenced by FcγR recognition of immunoglobulins and immune complexes in the steady state and during inflammation.

Within adipose tissue (AT), immune cells and parenchymal cells closely interact creating a complex microenvironment. In obesity, immune cell derived inflammation contributes to insulin resistance and glucose intolerance. Diet-induced weight loss improves glucose tolerance; however, weight regain further exacerbates the impairment in glucose homeostasis observed with obesity. To interrogate the immunometabolic adaptations that occur in AT during murine weight loss and weight regain, we utilized cellular indexing of transcriptomes and epitopes by sequencing (CITEseq) in male mice. Obesity-induced imprinting of AT immune cells persisted through weight-loss and progressively worsened with weight regain, ultimately leading to impaired recovery of type 2 regulatory cells, activation of antigen presenting cells, T cell exhaustion, and enhanced lipid handling in macrophages in weight cycled mice. This work provides critical groundwork for understanding the immunological causes of weight cycling-accelerated metabolic disease. For further discovery, we provide an open-access web portal of diet-induced AT immune cell imprinting: https://hastylab.shinyapps.io/MAIseq . Adipose immune cells contribute to obesity-related disease, but less is known about weight cycling. Here, authors show that weight loss reduces diabetes risk, but inflammatory adipose immune cell populations persist and may contribute to worsened diabetes risk upon weight regain.