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Currently three bona fide dendritic cell (DC) types are distinguished in human blood. Herein we focus on type 2 DCs (DC2s) and compare the three defining markers CD1c, CD172, and CD301. When using CD1c to define DC2s, a CD14 and a CD14 subset can be detected. The CD14 subset shares features with monocytes, and this includes substantially higher expression levels for CD64, CD115, CD163, and S100A8/9. We review the current knowledge of these CD1c CD14 cells as compared to the CD1c CD14 cells with respect to phenotype, function, transcriptomics, and ontogeny. Here, we discuss informative mutations, which suggest that two populations have different developmental requirements. In addition, we cover subsets of CD11c CD8 DC2s in the mouse, where CLEC12A ESAM cells, as compared to the CLEC12A ESAM subset, also express higher levels of monocyte-associated markers CD14, CD3, and CD115. Finally, we summarize, for both man and mouse, the data on lower antigen presentation and higher cytokine production in the monocyte-marker expressing DC2 subset, which demonstrate that the DC2 subsets are also functionally distinct.

Monocytes and dendritic cells regulate adaptive and innate immunity. This study uncovers an association between mutations in the gene encoding interferon regulatory factor 8 and deficiency of dendritic cells and monocytes in the context of disseminated bacille Calmette–Guérin disease. The discovery of human primary immunodeficiencies that affect the development of granulocytes, B cells, and T cells has been instrumental in defining the contribution of these cell types to protective immunity. 1 , 2 Monocytes, macrophages, and dendritic cells — all mononuclear phagocytes — have essential functions in both innate and acquired immunity. These cells initially recognize and engulf invading microbes, produce proinflammatory cytokines (e.g., interleukin-12), and process antigens for presentation to naive T cells, which consequently secrete various lymphokines (e.g., interferon-γ). 3 , 4 On activation by cytokines secreted by T cells, mononuclear phagocytes destroy ingested microorganisms. There are no known genetic causes . . .

Ikaros family zinc finger 1 (IKZF1) is a haematopoietic transcription factor required for mammalian B-cell development. IKZF1 deficiency also reduces plasmacytoid dendritic cell (pDC) numbers in mice, but its effects on human DC development are unknown. Here we show that heterozygous mutation of IKZF1 in human decreases pDC numbers and expands conventional DC1 (cDC1). Lenalidomide, a drug that induces proteosomal degradation of IKZF1, also decreases pDC numbers in vivo, and reduces the ratio of pDC/cDC1 differentiated from progenitor cells in vitro in a dose-dependent manner. In addition, non-classical monocytes are reduced by IKZF1 deficiency in vivo. DC and monocytes from patients with IKZF1 deficiency or lenalidomide-treated cultures secrete less IFN-α, TNF and IL-12. These results indicate that human DC development and function are regulated by IKZF1, providing further insights into the consequences of IKZF1 mutation on immune function and the mechanism of immunomodulation by lenalidomide. IKZF1 is a transcription factor known to regulate mammalian B-cell development. Here the authors show that IKZF1 is required for human pDC development and regulation of DC cytokine production in patients with IKZF1 haploinsufficiency, findings which are recapitulated in lenalidomide-induced IKZF1 deficiency.

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8-/-, but not Irf8+/-, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense.

Purpose X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by variants in Bruton’s tyrosine kinase ( BTK ). XLA patients require lifelong immunoglobulin replacement therapy (IgRT). Only few XLA patients are indicated for allogeneic hematopoietic cell transplantation (HCT) because of severe complications. Accordingly, the published transplantation experience in XLA is minimal. We aimed to collect clinical data of XLA patients who received HCT in an international framework and to establish appropriate transplantation criteria and methods for XLA patients. Methods XLA patients were recruited through a questionnaire and a literature review. The data are on patient characteristics and transplantation methods and outcomes. Results In this study, twenty-two XLA patients who underwent HCT were recruited. The indication for HCT was recurrent or life-threatening infection in sixteen patients, malignancy in three, and other factors in three. A myeloablative conditioning, reduced toxicity myeloablative conditioning (RT-MAC), and reduced intensity conditioning (RIC) were selected in four, ten, and eight patients, respectively. Engraftment was achieved in 21 patients (95%). In all patients, 2-year overall survival (OS) and event-free survival (EFS) were 86% and 77%, respectively. In patients who received RT-MAC or RIC using treosulfan, busulfan, or melphalan, 2-year OS and EFS were 82% and 71%, respectively. Finally, twenty-one patients (95%) obtained complete or stable high-level mixed chimerism (50–95%), and the 1-year discontinuation rate of IgRT was 89%. Conclusion Based on the concept in which IgRT is the standard treatment for XLA, HCT may be an effective and safe alternative treatment option for XLA patients, and IgRT can be discontinued following transplantation. It is ideal to perform HCT in XLA patients for whom transplantation is indicated before they develop organ damage.

Dendritic cells specialise in initiating adaptive immune responses. The CD1c+ subset in human beings is proposed to excel at CD4+ T cell priming. An equivalent population in mice has been shown to be heterogeneous and contain functionally distinct monocyte-related and conventional dendritic cell-related subpopulations. We aimed to examine whether analogous diversity exists in human beings using the conserved conventional dendritic cell marker, B and T lymphocyte attenuator (BTLA), which exhibits bimodal expression on CD1c+ dendritic cells. BTLA–CD1c+ and BTLA+CD1c+ dendritic cells were flow-sorted from peripheral blood. Gene expression (NanoString, Seattle, WA, USA), cytokine production after stimulation with lipopolysaccharide and R848 (Luminex, eBioscience, San Diego, CA, USA), and naive CD4+ T cell polarisation capacity (allogeneic mixed lymphocyte reaction assay) were compared. Their potential to differentiate into Langerhans cells (by culturing in granulocyte macrophage colony stimulating factor [GM-CSF] plus BMP7) and osteoclasts (by culturing in macrophage colony stimulating factor plus RANKL) in vitro was assessed. Their relative proportions in healthy blood and rheumatoid arthritis synovial fluid were compared by flow cytometry. CD1c+BTLA– dendritic cells had higher expression than CD1c+BTLA+ dendritic cells of typical monocyte genes (CD14, FCGR2A, S100A8, S100A9); they preferentially promoted interferon γ (mean 17·79% [SE 3·69] vs 7·21 [1·20], p=0·0094), interleukin (IL) 17 (5·10% [0·96] vs 2·30 [0·77], p=0·0015), and GM-CSF-producing T cells (34·39% [8·65] vs 18·31 [7·16], p=0·0066) and produced more IL1β (2517 pg/mL [241] vs 702·6 [206·4], p<0·0001) and IL18 (71·7 pg/mL [4·97] vs 48·07 [3·11], p=0·0016). CD1c+BTLA+ dendritic cells had higher expression than CD1c+BTLA– dendritic cells of conventional dendritic cell genes (CLEC9A, CD24, KIT) and preferentially promoted IL4-producing T cells (15·7% [2·06%] vs 11·7 [1·65], p=0·0059) and CD25hiFOXP3+ regulatory T cells (Tregs) (15·09% [4·18] vs 9·26 [2·48], p=0·0346). CD1c+BTLA– dendritic cells had greater potential to differentiate into tartrate-resistant acid phosphatase positive multinucleated osteoclasts whereas CD1c+BTLA+ dendritic cells preferentially differentiated into langerin+CD1a+ Langerhans cells. The ratio of CD1c+BTLA– to CD1c+BTLA+ dendritic cells was significantly higher in rheumatoid arthritis synovial fluid than in peripheral blood (3·76 [0·64] vs 1·11 [0·10], p<0·0001). CD1c-expressing dendritic cells have been regarded as a single population but these data demonstrate underlying complexity. CD1c+BTLA– dendritic cells support T helper (Th) 1 cell and Th17 cell responses and possess osteoclast potential. CD1c+BTLA+ dendritic cells support Th2 cell and Treg responses and possess Langerhans cell potential. The bulk CD1c+ population has previously been manipulated to produce vaccine and tolerogenic dendritic cell therapies in cancer and autoimmunity, but more refined targeting could potentially improve their efficacy. Wellcome Trust.

Key Points Dendritic cells (DCs) are crucial for the induction of immune responses in mice, but whether they are similarly essential in humans remains largely untested owing to the lack of appropriate models. Many human immunodeficiency states are known, but DC deficiency was only recently described. It is now appreciated that there are at least two forms of DC deficiency: due to mutation of GATA-binding factor 2 ( GATA2 ) or mutation of interferon regulatory factor 8 ( IRF8 ). Both lead to increased susceptibility to intracellular pathogens, notably mycobacteria. GATA2 mutation causes DC, monocyte, B and NK lymphoid (DCML) deficiency, which is characterized by the loss of DCs, monocytes, B cells and NK cells. It has been described in about 30 patients worldwide, and these patients progress from immunodeficiency to global bone marrow failure. IRF8 mutations have been reported in three patients. The recessive mutation K108E causes monocyte and DC deficiency with myeloproliferation, showing close similarities to IRF8-deficient mice. The study of DC deficiency has further potential to illuminate the genetic factors and cellular pathways of DC differentiation in humans and to uncover the relationship between DCs and monocytes. Much insight into the workings of the immune system has been garnered from studying patients with primary immunodeficiencies. This article describes the recent discovery of human dendritic cell deficiencies and explains the lessons we can learn from these syndromes. Animal models and human in vitro systems indicate that dendritic cells (DCs) have a crucial role in priming naive T cells, but just how important are they in the intact human? Recent descriptions of human DC deficiency have begun to shed light on this question and to illuminate other puzzles of human DC biology, including their haematopoietic origin, developmental regulation and homeostatic equilibrium with other leukocytes. In this Review, we explore the recently described DC deficiency syndromes, discussing what these have taught us with regard to DC function in humans and the important issues that remain unsolved.

Prenatal immune suppression is regulated by fetal arginase-2-expressing dendritic cells which respond normally to toll-like receptor stimulation but, in contrast to adult dendritic cells, induce regulatory T cells and repress TNF-α secretion by effector T cells. Fetal immunity How the immune system of a developing fetus responds to maternal and microbial antigens is not well understood. Florent Ginhoux and colleagues show that pre-natal immune suppression is regulated by fetal arginase-expressing dendritic cells, which respond normally to toll-like receptor stimulation but, in contrast to adult dendritic cells, induce regulatory rather than effector T cells. During gestation the developing human fetus is exposed to a diverse range of potentially immune-stimulatory molecules including semi-allogeneic antigens from maternal cells 1 , 2 , substances from ingested amniotic fluid 3 , 4 , food antigens 5 , and microbes 6 . Yet the capacity of the fetal immune system, including antigen-presenting cells, to detect and respond to such stimuli remains unclear. In particular, dendritic cells, which are crucial for effective immunity and tolerance, remain poorly characterized in the developing fetus. Here we show that subsets of antigen-presenting cells can be identified in fetal tissues and are related to adult populations of antigen-presenting cells. Similar to adult dendritic cells, fetal dendritic cells migrate to lymph nodes and respond to toll-like receptor ligation; however, they differ markedly in their response to allogeneic antigens, strongly promoting regulatory T-cell induction and inhibiting T-cell tumour-necrosis factor-α production through arginase-2 activity. Our results reveal a previously unappreciated role of dendritic cells within the developing fetus and indicate that they mediate homeostatic immune-suppressive responses during gestation.

Myelopoiesis is invariably present and contributes to pathology in animal models of graft-versus-host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties, and role in pathogenesis of these cells, we isolated single-cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome, and in vitro functional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and NanoString gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPα and S100A8/9 transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and costimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a keratinocyte cell line and mediated pathological damage to skin explants independently of T cells. Together, these results define the origin, functional properties, and potential pathogenic roles of human GVHD macrophages.