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ABSTRACT: Mucosal innate lymphoid cell (ILC) subsets promote immune responses to pathogens by producing distinct signature cytokines in response to changes in the cytokine microenvironment. We previously identified human ILC3 distinguished by interleukin-22 (IL-22) secretion. Here we characterized a human ILC1 subset that produced interferon-γ (IFN-γ) in response to IL-12 and IL-15 and had a unique integrin profile, intraepithelial location, hallmarks of TGF-β imprinting, and a memory-activated phenotype. Because tissue-resident memory CD8+ T cells share this profile, intraepithelial ILC1 may be their innate counterparts. In mice, intraepithelial ILC1 were distinguished by CD160 expression and required Nfil3- and Tbx21-encoded transcription factors for development, but not IL-15 receptor-α, indicating that intraepithelial ILC1 are distinct from conventional NK cells. Intraepithelial ILC1 were amplified in Crohn's disease patients and contributed to pathology in the anti-CD40-induced colitis model in mice. Thus, intraepithelial ILC1 may initiate IFN-γ responses against pathogens but contribute to pathology when dysregulated.
Immunity 02/2013; · 21.64 Impact Factor
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ABSTRACT: The differentiation of bone marrow-derived progenitor cells into monocytes, tissue macrophages and some dendritic cell (DC) subtypes requires the growth factor CSF1 and its receptor, CSF1R. Langerhans cells (LCs) and microglia develop from embryonic myeloid precursor cells that populate the epidermis and central nervous system (CNS) before birth. Notably, LCs and microglia are present in CSF1-deficient mice but absent from CSF1R-deficient mice. Here we investigated whether an alternative CSF1R ligand, interleukin 34 (IL-34), is responsible for this discrepancy. Through the use of IL-34-deficient (Il34(LacZ/LacZ)) reporter mice, we found that keratinocytes and neurons were the main sources of IL-34. Il34(LacZ/LacZ) mice selectively lacked LCs and microglia and responded poorly to skin antigens and viral infection of the CNS. Thus, IL-34 specifically directs the differentiation of myeloid cells in the skin epidermis and CNS.
Nature Immunology 06/2012; 13(8):753-60. · 26.01 Impact Factor
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ABSTRACT: Type I interferon (IFN-I) promotes antiviral CD8(+)T cell responses, but the contribution of different IFN-I sources and signaling pathways are ill defined. While plasmacytoid dendritic cells (pDCs) produce IFN-I upon TLR stimulation, IFN-I is induced in most cells by helicases like MDA5. Using acute and chronic lymphocytic choriomeningitis virus (LCMV) infection models, we determined that pDCs transiently produce IFN-I that minimally impacts CD8(+)T cell responses and viral persistence. Rather, MDA5 is the key sensor that induces IFN-I required for CD8(+)T cell responses. In the absence of MDA5, CD8(+)T cell responses to acute infection rely on CD4(+)T cell help, and loss of both CD4(+)T cells and MDA5 results in CD8(+)T cell exhaustion and persistent infection. Chronic LCMV infection rapidly attenuates IFN-I responses, but early administration of exogenous IFN-I rescues CD8(+)T cells, promoting viral clearance. Thus, effective antiviral CD8(+)T cell responses depend on the timing and magnitude of IFN-I production.
Cell host & microbe 06/2012; 11(6):631-42. · 13.02 Impact Factor
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ABSTRACT: Plasmacytoid dendritic cells (pDCs) have been associated with several names and functions over time, reflecting the limited
availability of specific markers and their ability to produce large amounts of type I interferons, present antigens, as well
as prime disparate T-cell helper responses. Yet, there is increasing evidence that pDCs are a distinct cell type in the innate
immune system. This review high-lights aspects in which pDCs are unique in comparison to other antigen-presenting cells in
regulating innate and adaptive immune responses.
Immunologic Research 04/2012; 32(1):75-83. · 3.03 Impact Factor
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ABSTRACT: Fc receptor-like (FcRL) proteins are a family of cellular receptors homologous to FcγRI and are predominantly expressed by B cells. They function to costimulate or inhibit BCR signaling through consensus ITAMs and ITIMs; however, the extracellular ligands of these receptors remain unknown or controversial. In this study, we tested the ability of human FcRL proteins to bind Igs and found FcRL4 and FcRL5 to be bona fide Fc receptors. In cellular binding assays, FcRL4 bound efficiently to IgA and FcRL5 binds all IgG isotypes with varied efficiency. Additionally, we generated mAbs capable of specifically blocking these interactions. Given their expression on activated B cells and potential for inhibitory signaling, FcRL4 and FcRL5 are likely to be important for immune complex-dependent human B cell regulation, and they represent novel therapeutic targets for receptor blockade therapies.
The Journal of Immunology 04/2012; 188(10):4741-5. · 5.79 Impact Factor
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ABSTRACT: Genome-wide studies have identified associations between polymorphisms in the IFN regulatory factor-5 (Irf5) gene and a variety of human autoimmune diseases. Its functional role in disease pathogenesis, however, remains unclear, as studies in Irf5(-/-) mice have reached disparate conclusions regarding the importance of this transcription factor in type I IFN production and antibody responses. We identified a spontaneous genomic duplication and frameshift mutation in the guanine exchange factor dedicator of cytokinesis 2 (Dock2) that has arisen in at least a subset of circulating Irf5(-/-) mice and inadvertently been bred to homozygosity. Retroviral expression of DOCK2, but not IRF-5, rescued defects in plasmacytoid dendritic cell and B-cell development, and Irf5(-/-) mice lacking the mutation in Dock2 exhibited normal plasmacytoid dendritic cell and B-cell development, largely intact type I IFN responses, and relatively normal antibody responses to viral infection. Thus, confirmation of the normal Dock2 genotype in circulating Irf5(-/-) mice is warranted, and our data may partly explain conflicting results in this field.
Proceedings of the National Academy of Sciences 03/2012; 109(15):E898-904. · 9.68 Impact Factor
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ABSTRACT: Bone marrow stromal Ag 2 (BST2) is a transmembrane protein that prevents virus release from infected cells. It was also reported that BST2 inhibits type I IFN production by plasmacytoid dendritic cells. To determine BST2 impact on antiviral responses in vivo, we generated BST2(-/-) mice. Following infection with a murine retrovirus, BST2(-/-) mice had slightly elevated viral loads; however, infection with other enveloped viruses revealed unexpected roles of BST2. BST2(-/-) mice showed reduced type I IFN production by plasmacytoid dendritic cells. Moreover, BST2(-/-) mice had lower viral titers in lungs following intranasal infection with vesicular stomatitis virus expressing OVA and influenza B and increased numbers of virus-specific CD8 T cells in the lungs, suggesting that BST2 may facilitate entry and/or replication of enveloped viruses and modulate priming of CD8 T cells. These findings suggest complex roles of BST2 beyond retroviral control in vivo, possibly reflecting the involvement of BST2 in endocytosis and intracellular trafficking of viruses, viral nucleic acids, and Ags.
The Journal of Immunology 03/2012; 188(6):2488-92. · 5.79 Impact Factor
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Karel Otero,
Masahiro Shinohara,
Haibo Zhao,
Marina Cella,
Susan Gilfillan,
Angela Colucci,
Roberta Faccio,
F Patrick Ross,
Steve L Teitelbaum,
Hiroshi Takayanagi, Marco Colonna
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ABSTRACT: TREM2 is an immunoreceptor expressed on osteoclasts (OC) and microglia that transmits intracellular signals through the adaptor DAP12. Individuals with genetic mutations inactivating TREM2 or DAP12 develop the Nasu-Hakola disease (NHD) with cystic-like lesions of the bone and brain demyelination that lead to fractures and presenile dementia. The mechanisms of this disease are poorly understood. In this study, we report that TREM2-deficient mice have an osteopenic phenotype reminiscent of NHD. In vitro, lack of TREM2 impairs proliferation and β-catenin activation in osteoclast precursors (OcP) in response to M-CSF. This defect results in accelerated differentiation of OcP into mature OC. Corroborating the importance of a balanced proliferation and differentiation of OcP for bone homeostasis, we show that conditional deletion of β-catenin in OcP also results in reduced OcP proliferation and accelerated osteoclastogenesis in vitro as well as osteopenia in vivo. These results reveal that TREM2 regulates the rate of osteoclastogenesis and provide a mechanism for the bone pathology in NHD.
The Journal of Immunology 03/2012; 188(6):2612-21. · 5.79 Impact Factor
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ABSTRACT: Mucosal innate lymphoid cells (ILCs) are an emerging population of diverse and heterogeneous immune cells, all with the unique ability to mount a rapid response against invading pathogens. They are further divided into subsets based on their differing cell surface markers as well as in their functional specialization. In this review, we summarize recent reports describing the importance of the transcription factor aryl hydrocarbon receptor (AHR) in regulating the development of one of these subsets, the Type-17/22 ILCs, as well as in the organization of postnatal lymphoid structures. We discuss the mechanisms behind the AHR dependence for development in Type-17/22 ILCs as well as reviewing the proposed physiological ligands that are mediating this effect.
Frontiers in immunology. 01/2012; 3:10.
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ABSTRACT: Type I interferons (IFN-I) were first described over 50 years ago as factors produced by cells that interfere with virus replication and promote an antiviral state. Innate and adaptive immune responses to viruses are also greatly influenced by IFN-I. In this article we discuss the diversity of cellular sources of IFN-I and the pathways leading to IFN-I production during viral infections. Finally, we discuss the effects of IFN-I on cells of the immune system with emphasis on dendritic cells.
Current opinion in virology. 12/2011; 1(6):463-75.
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Jacob S Lee,
Marina Cella,
Keely G McDonald,
Cecilia Garlanda,
Gregory D Kennedy,
Manabu Nukaya,
Alberto Mantovani,
Raphael Kopan,
Christopher A Bradfield,
Rodney D Newberry, Marco Colonna
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ABSTRACT: Innate lymphoid cells (ILCs) of the ILC22 type protect the intestinal mucosa from infection by secreting interleukin 22 (IL-22). ILC22 cells include NKp46(+) and lymphoid tissue-inducer (LTi)-like subsets that express the aryl hydrocarbon receptor (AHR). Here we found that Ahr(-/-) mice had a considerable deficit in ILC22 cells that resulted in less secretion of IL-22 and inadequate protection against intestinal bacterial infection. Ahr(-/-) mice also lacked postnatally 'imprinted' cryptopatches and isolated lymphoid follicles (ILFs), but not embryonically 'imprinted' Peyer's patches. AHR induced the transcription factor Notch, which was required for NKp46(+) ILCs, whereas LTi-like ILCs, cryptopatches and ILFs were partially dependent on Notch signaling. Thus, AHR was essential for ILC22 cells and postnatal intestinal lymphoid tissues. Moreover, ILC22 subsets were heterogeneous in their requirement for Notch and their effect on the generation of intestinal lymphoid tissues.
Nature Immunology 11/2011; 13(2):144-51. · 26.01 Impact Factor
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ABSTRACT: Plasmacytoid dendritic cells (pDCs) specialize in the secretion of type I interferons (IFN-I) and thus are considered critical mediators of antiviral responses. We recently reported that pDCs have a very early but limited and transient capacity to curtail viral infections. Additionally, pDC numbers are not sustained in human infections caused by Hepatitis B or C viruses (HBV and HCV) and HIV. Thus, the numbers and/or function of pDCs appear to be regulated during the course of viral infection. In this study, we show that splenic pDCs are reduced in vivo during several systemic viral infections and after administration of synthetic toll-like receptor ligands. We demonstrate that IFN-I, regardless of the source, contributes to this decline and mediates pDC death via the intrinsic apoptosis pathway. These findings demonstrate a feedback control mechanism by which IFN-I modulates pDC numbers, thus fine-tuning systemic IFN-I response to viruses. IFN-I-mediated control of pDCs may explain the loss of pDCs during human infections caused by HBV, HCV, or HIV and has important therapeutic implications for settings in which IFN-I is used to treat infections and autoimmune diseases.
Journal of Experimental Medicine 11/2011; 208(12):2367-74. · 13.85 Impact Factor
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ABSTRACT: The innate immune system detects viruses through molecular sensors that trigger the production of type I interferons (IFN-I) and inflammatory cytokines. As viruses vary tremendously in size, structure, genomic composition, and tissue tropism, multiple sensors are required to detect their presence in various cell types and tissues. In this review, we summarize current knowledge of the diversity, specificity, and signaling pathways downstream of viral sensors and ask whether two distinct sensors that recognize the same viral component are complementary, compensatory, or simply redundant. We also discuss why viral sensors are differentially distributed in distinct cell types and whether a particular cell type dominates the IFN-I response during viral infection. Finally, we review evidence suggesting that inappropriate signaling through viral sensors may induce autoimmunity. The picture emerging from these studies is that disparate viral sensors in different cell types form a dynamic and integrated molecular network that can be exploited for improving vaccination and therapeutic strategies for infectious and autoimmune diseases.
Immunological Reviews 09/2011; 243(1):74-90. · 11.15 Impact Factor
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ABSTRACT: Plasmacytoid dendritic cells are specialized in the production of type I interferon (type I IFN), which promotes antiviral and antitumor responses, as well as autoimmune disorders. Activation of type I IFN secretion depends on the pattern recognition receptors TLR7 and TLR9, which sense microbial RNA and DNA, respectively. Type I IFN production is modulated by several receptors, including the type II C-type lectin domain family 4, member C (CLEC4C). The natural ligand of CLEC4C is unknown. To identify it, here we probed a glycan array with a soluble form of the CLEC4C ectodomain. We found that CLEC4C recognizes complex type sugars with terminal galactose. Importantly, soluble CLEC4C bound peripheral blood leukocytes and tumor cells that express glycans with galactose residues at the non-reducing ends. The positive and negative modulation of galactose residues on cell membranes was paralleled by the regulation of type I IFN secretion by plasmacytoid dendritic cells in co-culture experiments in vitro. These results suggest that the modulation in the expression of non-sialylated oligosaccharides by invading pathogens or transformed cells may affect type I IFN response and immune surveillance.
Journal of Biological Chemistry 08/2011; 286(41):35329-33. · 4.77 Impact Factor
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ABSTRACT: IFN-I are pleiotropic cytokines that impact innate and adaptive immune responses. In this article, we discuss TLR7/9 versus TLR3/MDA5 signaling in antiviral responses and diabetes. pDCs are thought to have a critical role in antiviral defense because of their ability to rapidly secrete large amounts of IFN-I through TLR7/9 signaling. A recent study demonstrates that although pDCs are a source of IFN-I in vivo, their overall contribution to viral containment is limited and time-dependent, such that additional cellular sources of IFN-I are required to fully control viral infections. dsRNA sensors, such as TLR3 and MDA5, provide another important trigger for antiviral IFN-I responses, which can be exploited to enhance immune responses to vaccines. In the absence of infection, IFN-I production by pDCs or from signaling through dsRNA sensors has been implicated in the pathogenesis of autoimmune diseases such as diabetes. However, recent data demonstrate that IFN-I production via TLR3 and MDA5 is critical to counter diabetes caused by a virus with preferential tropism for pancreatic β-cells. This highlights the complexity of the host antiviral response and how multiple cellular and molecular components balance protective versus pathological responses.
Journal of leukocyte biology 08/2011; 90(4):691-701. · 4.99 Impact Factor
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ABSTRACT: Viral infections have been linked to the onset of type I diabetes (T1D), with viruses postulated to induce disease directly by causing β cell injury and subsequent release of autoantigens and indirectly via the host type I interferon (IFN-I) response triggered by the virus. Consistent with this, resistance to T1D is associated with polymorphisms that impair the function of melanoma differentiation associated gene-5 (MDA5), a sensor of viral RNA that elicits IFN-I responses. In animal models, triggering of another viral sensor, TLR3, has been implicated in diabetes. Here, we found that MDA5 and TLR3 are both required to prevent diabetes in mice infected with encephalomyocarditis virus strain D (EMCV-D), which has tropism for the insulin-producing β cells of the pancreas. Infection of Tlr3-/- mice caused diabetes due to impaired IFN-I responses and virus-induced β cell damage rather than T cell-mediated autoimmunity. Mice lacking just 1 copy of Mda5 developed transient hyperglycemia when infected with EMCV-D, whereas homozygous Mda5-/- mice developed severe cardiac pathology. TLR3 and MDA5 controlled EMCV-D infection and diabetes by acting in hematopoietic and stromal cells, respectively, inducing IFN-I responses at kinetically distinct time points. We therefore conclude that optimal functioning of viral sensors and prompt IFN-I responses are required to prevent diabetes when caused by a virus that infects and damages the β cells of the pancreas.
The Journal of clinical investigation 03/2011; 121(4):1497-507. · 15.39 Impact Factor
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ABSTRACT: Molluscum contagiosum virus (MCV) is a poxvirus that causes tumor-like skin lesions. New evidence indicates that plasmacytoid dendritic cells, type I interferon production, and interferon-induced dendritic cells have prominent roles in anti-MCV responses, and these features characterize the inflammatory response in lesions that will likely undergo spontaneous regression.
Journal of Investigative Dermatology 02/2011; 131(2):288-90. · 6.31 Impact Factor
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ABSTRACT: More than 450 immunologists recently met in Cavtat, Croatia to discuss advances in natural killer (NK) cell biology. The meeting highlighted emerging themes in NK cell responses to viruses, NK cell tolerance and potential use of NK cells in the therapy of malignancies.
Nature Immunology 02/2011; 12(2):107-10. · 26.01 Impact Factor
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ABSTRACT: Plasmacytoid dendritic cells (pDCs) were first described as interferon-producing cells and, for many years, their overlapping characteristics with both lymphocytes and classical dendritic cells (cDCs) created confusion over their exact ontogeny. In this Viewpoint article, Nature Reviews Immunology asks five leaders in the field to discuss their thoughts on the development and functions of pDCs--do these cells serve mainly as a major source of type I interferons or do they also make other important contributions to immune responses?
Nature Reviews Immunology 01/2011; 11(8):558-65. · 32.25 Impact Factor
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Marco Colonna
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ABSTRACT: Human CD4+ T cells that produce interleukin 22 are an essential component of skin defense and repair. New evidence shows that these T cells recognize CD1a-lipid complexes on Langerhans cells.
Nature Immunology 12/2010; 11(12):1079-80. · 26.01 Impact Factor
