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2.
PLoS Pathog ; 13(1): e1006120, 2017 01.
Article in English | MEDLINE | ID: mdl-28046066

ABSTRACT

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. To enhance cell-to-cell transmission of HTLV-1, the virus increases the number of infected cells in vivo. HTLV-1 bZIP factor (HBZ) is constitutively expressed in HTLV-1 infected cells and ATL cells and promotes T-cell proliferation. However, the detailed mechanism by which it does so remains unknown. Here, we show that HBZ enhances the proliferation of expressing T cells after stimulation via the T-cell receptor. HBZ promotes this proliferation by influencing the expression and function of multiple co-inhibitory receptors. HBZ suppresses the expression of BTLA and LAIR-1 in HBZ expressing T cells and ATL cells. Expression of T cell immunoglobulin and ITIM domain (TIGIT) and Programmed cell death 1 (PD-1) was enhanced, but their suppressive effect on T-cell proliferation was functionally impaired. HBZ inhibits the co-localization of SHP-2 and PD-1 in T cells, thereby leading to impaired inhibition of T-cell proliferation and suppressed dephosphorylation of ZAP-70 and CD3ζ. HBZ does this by interacting with THEMIS, which associates with Grb2 and SHP-2. Thus, HBZ interacts with the SHP containing complex, impedes the suppressive signal from PD-1 and TIGIT, and enhances the proliferation of T cells. Although HBZ was present in both the nucleus and the cytoplasm of T cells, HBZ was localized largely in the nucleus by suppressed expression of THEMIS by shRNA. This indicates that THEMIS is responsible for cytoplasmic localization of HBZ in T cells. Since THEMIS is expressed only in T-lineage cells, HBZ mediated inhibition of the suppressive effects of co-inhibitory receptors accounts for how HTLV-1 induces proliferation only of T cells in vivo. This study reveals that HBZ targets co-inhibitory receptors to cause the proliferation of infected cells.


Subject(s)
Basic-Leucine Zipper Transcription Factors/metabolism , Cell Proliferation/physiology , HTLV-I Infections/transmission , Human T-lymphotropic virus 1/pathogenicity , Proteins/metabolism , Retroviridae Proteins/metabolism , T-Lymphocytes/immunology , Animals , Basic-Leucine Zipper Transcription Factors/genetics , CD3 Complex/metabolism , Cell Line, Tumor , Encephalomyelitis, Autoimmune, Experimental/virology , GRB2 Adaptor Protein/metabolism , HTLV-I Infections/virology , Humans , Intercellular Signaling Peptides and Proteins , Jurkat Cells , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Programmed Cell Death 1 Receptor/biosynthesis , Programmed Cell Death 1 Receptor/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Receptors, Immunologic/biosynthesis , Receptors, Immunologic/metabolism , Retroviridae Proteins/genetics , ZAP-70 Protein-Tyrosine Kinase/metabolism
3.
Eur J Immunol ; 47(4): 704-712, 2017 04.
Article in English | MEDLINE | ID: mdl-28127756

ABSTRACT

Dendritic cell immunoreceptor (DCIR) is a C-type lectin with an immunoreceptor tyrosine-based inhibitory motif (ITIM). Mice lacking DCIR1 (Dcir1-/- mice) show higher susceptibility to chronic arthritis with increasing age, suggesting that DCIR1 is involved in immune modulation via its ITIM. However, the role of DCIR1 in acute immune responses is not clear. In this study, we explored its role in acute experimental hepatitis. Upon injection of d-galactosamine and lipopolysaccharide, Dcir1-/- mice showed decreased mortality rates and serum levels of alanine aminotransferase. In early onset hepatitis, serum levels of TNF-α, which primarily cause inflammation and hepatocyte apoptosis, were significantly lower in Dcir1-/- mice than in WT mice. In the liver of Dcir1-/- mice, influx of neutrophils and other leukocytes decreased. Consistently, the levels of neutrophil-chemoattractant chemokine CXCL1/KC, but not CXCL2/MIP-2, were lower in Dcir1-/- mice than in WT mice. However, chemotaxis of Dcir1-/- neutrophils to CXCL1/KC appeared normal. Pervanadate treatment induced binding of DCIR1 and Src homology region 2 domain-containing phosphatase (SHP)-2, possibly leading to CXCL1/KC expression. These results suggest that DCIR1 is involved in exacerbation of endotoxemic hepatitis, providing a new therapeutic target for lethal hepatitis.


Subject(s)
Chemical and Drug Induced Liver Injury/immunology , Dendritic Cells/physiology , Endotoxemia/immunology , Lectins, C-Type/metabolism , Neutrophils/immunology , Animals , Cell Movement/genetics , Cells, Cultured , Chemical and Drug Induced Liver Injury/drug therapy , Chemokine CXCL1/metabolism , Chemokine CXCL2/metabolism , Endotoxemia/drug therapy , Galactosamine/administration & dosage , Humans , Lectins, C-Type/genetics , Lipopolysaccharides/administration & dosage , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Targeted Therapy , Vanadates/pharmacology
5.
BMC Immunol ; 16: 64, 2015 Oct 23.
Article in English | MEDLINE | ID: mdl-26497661

ABSTRACT

BACKGROUND: Ulcerative colitis, an inflammatory bowel disease, is associated with the massive infiltration of neutrophils. Although the initial infiltration of neutrophils is beneficial for killing bacteria, it is presumed that persistent infiltration causes tissue damage by releasing antibacterial products as well as inflammatory cytokines. A murine C-type lectin receptor, dendritic cell immunoreceptor 1 (Dcir1), is expressed on CD11b(+) myeloid cells, such as macrophages, dendritic cells and neutrophils. It was reported that Dcir1 is required to maintain homeostasis of the immune system to prevent autoimmunity, but it is also involved in the development of infectious disease resulting in the enhanced severity of cerebral malaria. However, the role of Dcir1 in intestinal immune responses during colitis remains unclear. In this study, we investigated the role of Dcir1 in intestinal inflammation using an experimental colitis model induced with dextran sodium sulfate (DSS). RESULTS: In contrast to wild type (WT) mice, Dcir1 (-/-) mice exhibited mild body weight loss during the course of DSS colitis accompanied by reduced colonic inflammation. Dcir1 deficiency caused a reduced accumulation of neutrophils in the inflamed colon on day 5 of DSS colitis compared with WT mice. Consistently, the production of a neutrophil-attracting chemokine, MIP-2, was also decreased in the Dcir1 (-/-) colon compared with the WT colon on day 5. There were fewer myeloperoxidase-positive neutrophils in the inflamed colon of Dcir1 (-/-) mice than in that of WT mice. Moreover, bone marrow neutrophils from Dcir1 (-/-) mice produced less reactive oxygen species (ROS) by lipopolysaccharide stimulation than those from WT mice. This suggests that Dcir1 deficiency decreases the accumulation of tissue destructive neutrophils during DSS colitis. CONCLUSION: Dcir1 enhances the pathogenesis of DSS colitis by altering neutrophil recruitment and their functions.


Subject(s)
Colitis/etiology , Colitis/metabolism , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Animals , Chemokine CXCL2/biosynthesis , Colitis/pathology , Cytokines/metabolism , Dextran Sulfate/adverse effects , Disease Models, Animal , Leukocyte Count , Lipopolysaccharides/immunology , Mice , Mice, Knockout , Neutrophil Infiltration/genetics , Neutrophil Infiltration/immunology , Peroxidase/metabolism , Reactive Oxygen Species/metabolism , Respiratory Burst/genetics , Respiratory Burst/immunology
6.
Immunol Lett ; 168(2): 300-5, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26481266

ABSTRACT

Conventional dendritic cells (cDCs) present α-galactosylceramide (αGC) to invariant natural killer T (iNKT) cells through CD1d. Among cDC subsets, CD8(+) DCs efficiently induce IFN-γ production in iNKT cells. Using fluorescence-labeled αGC, we showed that CD8(+) DCs incorporated larger amounts of αGC and kept it intact longer than CD8(-) DCs. Histological analyses revealed that Langerin(+)CD8(+) DCs in the splenic marginal zone, which was the unique equipment to capture blood-borne antigens, preferably incorporated αGC, and the depletion of Langerin(+) cells decreased IFN-γ and IL-12 production in response to αGC. Furthermore, splenic Langerin(+)CD8(+) DCs expressed more membrane-bound CXCL16, which possibly anchored iNKT cells in the marginal zone, than CD8(-) DCs. Collectively, it is suggested that the cellular properties and localization of CD8(+) DCs are important for stimulation of iNKT cells by αGC.


Subject(s)
Dendritic Cells/immunology , Fluorescence , Galactosylceramides/immunology , Animals , Antigens, Surface/immunology , Antigens, Surface/metabolism , CD8 Antigens/immunology , CD8 Antigens/metabolism , Carbocyanines/chemistry , Chemokine CXCL16 , Chemokine CXCL6/immunology , Chemokine CXCL6/metabolism , Coculture Techniques , Dendritic Cells/cytology , Dendritic Cells/metabolism , Flow Cytometry , Fluorescent Dyes/chemistry , Galactosylceramides/metabolism , Galactosylceramides/pharmacokinetics , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-12/immunology , Interleukin-12/metabolism , Lectins, C-Type/immunology , Lectins, C-Type/metabolism , Mannose-Binding Lectins/immunology , Mannose-Binding Lectins/metabolism , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Natural Killer T-Cells/cytology , Natural Killer T-Cells/immunology , Natural Killer T-Cells/metabolism , Spleen/cytology , Spleen/immunology , Spleen/metabolism
7.
Biochem Biophys Res Commun ; 458(3): 561-567, 2015 Mar 13.
Article in English | MEDLINE | ID: mdl-25680460

ABSTRACT

Amyloid ß (Aß) peptide, a causative agent of Alzheimer's disease, forms two types of aggregates: oligomers and fibrils. These aggregates induce inflammatory responses, such as interleukin-1ß (IL-1ß) production by microglia, which are macrophage-like cells located in the brain. In this study, we examined the effect of the two forms of Aß aggregates on IL-1ß production in mouse primary microglia. We prepared Aß oligomer and fibril from Aß (1-42) peptide in vitro. We analyzed the characteristics of these oligomers and fibrils by electrophoresis and atomic force microscopy. Interestingly, Aß oligomers but not Aß monomers or fibrils induced robust IL-1ß production in the presence of lipopolysaccharide. Moreover, Aß oligomers induced endo/phagolysosome rupture, which released cathepsin B into the cytoplasm. Aß oligomer-induced IL-1ß production was inhibited not only by the cathepsin B inhibitor CA-074-Me but also by the reactive oxygen species (ROS) inhibitor N-acetylcysteine. Random chemical crosslinking abolished the ability of the oligomers to induce IL-1ß. Thus, multimerization and fibrillization causes Aß oligomers to lose the ability to induce IL-1ß. These results indicate that Aß oligomers, but not fibrils, induce IL-1ß production in primary microglia in a cathepsin B- and ROS-dependent manner.


Subject(s)
Amyloid beta-Peptides/immunology , Cathepsin B/immunology , Interleukin-1beta/immunology , Microglia/immunology , Peptide Fragments/immunology , Reactive Oxygen Species/immunology , Acetylcysteine/pharmacology , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/ultrastructure , Animals , Cathepsin B/antagonists & inhibitors , Cross-Linking Reagents/chemistry , Dipeptides/pharmacology , Mice , Mice, Inbred BALB C , Microglia/drug effects , Peptide Fragments/chemistry , Peptide Fragments/ultrastructure
8.
Sci Rep ; 4: 6030, 2014 Aug 12.
Article in English | MEDLINE | ID: mdl-25112380

ABSTRACT

Skin-derived dendritic cells (DCs) play a crucial role in the maintenance of immune homeostasis due to their role in antigen trafficking from the skin to the draining lymph nodes (dLNs). To quantify the spatiotemporal regulation of skin-derived DCs in vivo, we generated knock-in mice expressing the photoconvertible fluorescent protein KikGR. By exposing the skin or dLN of these mice to violet light, we were able to label and track the migration and turnover of endogenous skin-derived DCs. Langerhans cells and CD103(+)DCs, including Langerin(+)CD103(+)dermal DCs (DDCs), remained in the dLN for 4-4.5 days after migration from the skin, while CD103(-)DDCs persisted for only two days. Application of a skin irritant (chemical stress) induced a transient >10-fold increase in CD103(-)DDC migration from the skin to the dLN. Tape stripping (mechanical injury) induced a long-lasting four-fold increase in CD103(-)DDC migration to the dLN and accelerated the trafficking of exogenous protein antigens by these cells. Both stresses increased the turnover of CD103(-)DDCs within the dLN, causing these cells to die within one day of arrival. Therefore, CD103(-)DDCs act as sentinels against skin invasion that respond with increased cellular migration and antigen trafficking from the skin to the dLNs.


Subject(s)
Dendritic Cells/cytology , Lymph Nodes/cytology , Skin/cytology , Animals , Antigens, CD/metabolism , Cell Movement , Dendritic Cells/immunology , Dendritic Cells/metabolism , Dermatitis, Irritant/immunology , Dermatitis, Irritant/pathology , Gene Knock-In Techniques , Integrin alpha Chains/metabolism , Langerhans Cells/cytology , Langerhans Cells/immunology , Langerhans Cells/metabolism , Light , Lymph Nodes/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microscopy, Fluorescence , Proteins/genetics , Receptors, CCR7/deficiency , Receptors, CCR7/genetics , Receptors, CCR7/metabolism , Skin/immunology , Skin/metabolism
9.
J Biol Chem ; 289(3): 1564-79, 2014 Jan 17.
Article in English | MEDLINE | ID: mdl-24297165

ABSTRACT

Sialic acids (Sias) are often conjugated to the termini of cellular glycans and are key mediators of cellular recognition. Sias are nine-carbon acidic sugars, and, in vertebrates, the major species are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), differing in structure at the C5 position. Previously, we described a positive feedback loop involving regulation of Neu5Gc expression in mouse B cells. In this context, Neu5Gc negatively regulated B-cell proliferation, and Neu5Gc expression was suppressed upon activation. Similarly, resting mouse T cells expressed principally Neu5Gc, and Neu5Ac was induced upon activation. In the present work, we used various probes to examine sialoglycan expression by activated T cells in terms of the Sia species expressed and the linkages of Sias to glycans. Upon T-cell activation, sialoglycan expression shifted from Neu5Gc to Neu5Ac, and the linkage shifted from α2,6 to α2,3. These changes altered the expression levels of sialic acid-binding immunoglobulin-like lectin (siglec) ligands. Expression of sialoadhesin and Siglec-F ligands increased, and that of CD22 ligands decreased. Neu5Gc exerted a negative effect on T-cell activation, both in terms of the proliferative response and in the context of activation marker expression. Suppression of Neu5Gc expression in mouse T and B cells prevented the development of nonspecific CD22-mediated T cell-B cell interactions. Our results suggest that an activation-dependent shift from Neu5Gc to Neu5Ac and replacement of α2,6 by α2,3 linkages may regulate immune cell interactions at several levels.


Subject(s)
B-Lymphocytes/metabolism , Cell Communication/physiology , Lymphocyte Activation/physiology , Sialic Acids/metabolism , T-Lymphocytes/metabolism , Animals , Antigens, Differentiation, Myelomonocytic/biosynthesis , Antigens, Differentiation, Myelomonocytic/genetics , Antigens, Differentiation, Myelomonocytic/immunology , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cells, Cultured , Gene Expression Regulation/physiology , Mice , Mice, Knockout , Sialic Acid Binding Ig-like Lectin 2/biosynthesis , Sialic Acid Binding Ig-like Lectin 2/genetics , Sialic Acid Binding Ig-like Lectin 2/immunology , Sialic Acid Binding Immunoglobulin-like Lectins , Sialic Acids/genetics , Sialic Acids/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology
10.
J Immunol ; 191(6): 3152-60, 2013 Sep 15.
Article in English | MEDLINE | ID: mdl-23966631

ABSTRACT

All-trans-retinoic acid (RA) plays a critical role in maintaining immune homeostasis. Mouse intestinal CD103⁺ dendritic cells (DCs) produce a high level of RA by highly expressing retinal dehydrogenase (RALDH)2, an enzyme that converts retinal to RA, and induce gut-homing T cells. However, it has not been identified which subset of human DCs produce a high level of RA. In this study, we show that CD1c⁺ blood myeloid DCs (mDCs) but not CD141(high) mDCs or plasmacytoid DCs exhibited a high level of RALDH2 mRNA and aldehyde dehydrogenase (ALDH) activity in an RA- and p38-dependent manner when stimulated with 1α,25-dihydroxyvitamin D3 (VD3) in the presence of GM-CSF. The ALDH activity was abrogated by TLR ligands or TNF. CD103⁻ rather than CD103⁺ human mesenteric lymph node mDCs gained ALDH activity in response to VD3. Furthermore, unlike in humans, mouse conventional DCs in the spleen and mesenteric lymph nodes gained ALDH activity in response to GM-CSF alone. RALDH2(high) CD1c⁺ mDCs stimulated naive CD4⁺ T cells to express gut-homing molecules and to produce Th2 cytokines in an RA-dependent manner. This study suggests that CD1c⁺ mDCs are a major human DC subset that produces RA in response to VD3 in the steady state. The "vitamin D-CD1c⁺mDC-RA" axis may constitute an important immune component for maintaining tissue homeostasis in humans.


Subject(s)
Antigens, CD1/metabolism , Cholecalciferol/pharmacology , Dendritic Cells/metabolism , Glycoproteins/metabolism , Myeloid Cells/metabolism , Tretinoin/metabolism , Aldehyde Dehydrogenase/metabolism , Aldehyde Dehydrogenase 1 Family , Animals , Antigens, CD1/immunology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Glycoproteins/immunology , Humans , Mice , Myeloid Cells/immunology , Real-Time Polymerase Chain Reaction , Retinal Dehydrogenase/metabolism , Reverse Transcriptase Polymerase Chain Reaction
11.
PLoS One ; 8(7): e68499, 2013.
Article in English | MEDLINE | ID: mdl-23874646

ABSTRACT

Macrophages (Mϕ) are well documented to produce IL-1ß through various signaling pathways in response to small particles such as silica, asbestos and urea crystals, in the presence of lipopolysaccharide (LPS). However, it has not been clear to what extent particle size affects the response. To investigate this point, we stimulated bone marrow-derived macrophages (BMDM) with size-defined latex beads (LxB). Although both nano-sized (20 nm) and micro-sized (1,000 nm) LxB induced IL-1ß production, only the nano-sized particles formed large intracellular vacuoles. In contrast, 100 nm LxB did not induce either of the responses. The same cellular responses were also observed in primary microglia cells. Although K(+) efflux and NLRP3 activation in BMDM were crucial in response to both 20 and 1,000 nm LxB, only IL-1ß production by 20 nm LxB was sensitive to cathepsin B and P2X7, a receptor for ATP. The response by 1,000 nm LxB relied on a robust production of reactive oxygen species (ROS), since IL-1ß production was remarkably reduced by ROS inhibitors such as diphenylene iodonium (DPI) and N-acetylcysteine (NAC). In contrast, IL-1ß production by 20 nm LxB was augmented by NAC and in BMDM deficient in thioredoxin-binding protein-2 (TBP-2), a negative regulator of the ROS scavenger thioredoxin. These results suggest that the cells responded differently in their secretion of IL-1ß depending on particle size, and that there is a range within which neither pathway works.


Subject(s)
Interleukin-1beta/biosynthesis , Macrophages/immunology , Macrophages/metabolism , Microspheres , Particle Size , Acetylcysteine , Adenosine Triphosphate/metabolism , Animals , Cathepsin B/metabolism , Lipopolysaccharides , Macrophages/cytology , Mice , Phagosomes/metabolism , Reactive Oxygen Species/metabolism , Receptors, Purinergic P2X7/metabolism , Signal Transduction
12.
Immunity ; 38(5): 943-57, 2013 May 23.
Article in English | MEDLINE | ID: mdl-23623382

ABSTRACT

Macrophage and dendritic cell (DC) progenitors (MDPs) and common DC progenitors (CDPs) are bone marrow (BM) progenitors with DC differentiation potential. However, both MDPs and CDPs give rise to large numbers of conventional DCs (cDCs) and few plasmacytoid DCs (pDCs), implying that more dedicated pDC progenitors remain to be identified. Here we have described DC progenitors with a prominent pDC differentiation potential. Although both MDPs and CDPs express the macrophage colony stimulating factor (M-CSF) receptor (M-CSFR), the progenitors were confined to a M-CSFR(-) fraction, identified as Lin(-)c-Kit(int/lo)Flt3(+)M-CSFR(-), and expressed high amounts of E2-2 (also known as Tcf4) an essential transcription factor for pDC development. Importantly, they appeared to be directly derived from either CDPs or lymphoid-primed multipotent progenitors (LMPPs). Collectively, our findings provide insight into DC differentiation pathways and may lead to progenitor-based therapeutic applications for infection and autoimmune disease.


Subject(s)
Dendritic Cells/metabolism , Lymphoid Progenitor Cells/metabolism , Lymphopoiesis/immunology , Macrophages/metabolism , Receptor, Macrophage Colony-Stimulating Factor , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/biosynthesis , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Bone Marrow Cells/metabolism , Cell Differentiation/immunology , Dendritic Cells/cytology , Dendritic Cells/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Lymphoid Progenitor Cells/immunology , Lymphopoiesis/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptor, Macrophage Colony-Stimulating Factor/biosynthesis , Receptor, Macrophage Colony-Stimulating Factor/deficiency , Receptor, Macrophage Colony-Stimulating Factor/genetics , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Transcription Factor 4 , fms-Like Tyrosine Kinase 3/metabolism
13.
Int Immunol ; 25(6): 373-82, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23411727

ABSTRACT

Fas (CD95), a member of the tumor necrosis factor receptor superfamily, mediates apoptosis-inducing signals in its expressing cells, especially in self-reactive cells. We recently reported that Fas(-/-) mice with a BALB/c background (BALB/c Fas(-/-) mice) developed blepharitis with allergic inflammation that was accompanied by hyper-IgE production. Here, we found a novel type of immunocyte in the spleen of BALB/c Fas(-/-) mice, which enhanced the production of IgE by B cells in the presence of IL-4 and CD40 signaling in vitro. The immunocyte did not express lineage markers but expressed Thy-1 and Sca-1 just like recently identified type 2 innate lymphoid cells, such as natural helper (NH) cells and nuocytes. However, they did not express c-Kit, IL-7R and IL-33R (T1/ST2), important markers of type 2 innate lymphoid cells. Instead, our identified Lin(-)Thy-1(+)Sca-1(+) cells expressed IL-18R and secreted Th2 cytokines when co-cultured with B cells or when stimulated with IL-18 and IL-2. Moreover, we found essentially the same type of cells in BALB/c wild-type mice as in BALB/c Fas(-/-) mice, which enhanced IgE production in contact with B cells in vitro. These cells from BALB/c wild-type mice expressed Fas and were sensitive to Fas-mediated apoptosis. Collectively, the newly identified Lin(-)Thy-1(+)Sca-1(+) cell, which we designated a F-NH cell (Fas-expressing natural helper cell), is a novel type 2 innate immunocyte with activity to enhance IgE production from B cells with the help of IL-4 and CD40 signaling. F-NH cells may play an important role in the development of chronic allergic inflammation.


Subject(s)
Immunity, Innate/immunology , Immunoglobulin E/biosynthesis , Lymphocytes/immunology , Animals , Cells, Cultured , Immunoglobulin E/immunology , Lymphocytes/cytology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , fas Receptor/deficiency , fas Receptor/metabolism
14.
Int Immunol ; 24(9): 573-81, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22773153

ABSTRACT

Interferon regulatory factor (IRF)-2 is a transcription factor involved in type I (IFN- α/ß) signaling. It has been reported that IRF-2 deficiency results in various immune dysfunctions. However, the role of IRF-2 in B-cell functions needs to be elucidated. Unlike wild-type (WT) B cells, IRF-2(-/-) B2 cells were refractory to anti-IgM, but not LPS. Such a defect in proliferation was dependent on IFN- α/ß receptor (IFNAR). Marginal zone B cells increased in the proportion relative to B2 cells in IRF-2(-/-) mice produced IgM normally to LPS stimulation. However, IRF-2(-/-) B2 cells were defective in IgM production in an IFNAR-independent manner, although both B-cell subsets differentiated phenotypically to plasma cells at elevated efficiencies. Class switch recombination of IRF-2(-/-) B2 cells by LPS plus IL-4 was also impaired. Their reduced IgM production was conceivably due to an inefficient up-regulation of Blimp-1. Consistent with these in vitro observations, specific antibody production in vivo to a T-dependent antigen by B2 cells was severely impaired in IRF-2(-/- )mice. However, a low, but significant, level of IgG was detected at a late time point, and this IgG exhibited comparable binding affinity to that in WT mice. Follicular helper T-cell development and germinal center formation were normal. A similar tendency was observed when µ chain(-/-) mice were reconstituted with IRF-2(-/- )B cells. These results revealed a multi-faceted role of IRF-2 in the function of B cells, particularly B2 cells, through regulating proliferation in an IFNAR-dependent manner and antibody production via up-regulation of Blimp-1.


Subject(s)
B-Lymphocytes/immunology , Interferon Regulatory Factor-2/metabolism , Plasma Cells/immunology , Receptor, Interferon alpha-beta/metabolism , Transcription Factors/metabolism , Animals , Antibody Formation/genetics , B-Lymphocytes/transplantation , Cell Differentiation/genetics , Cell Proliferation , Cells, Cultured , Gene Expression Regulation , Immunoglobulin Class Switching/genetics , Immunoglobulin mu-Chains/genetics , Interferon Regulatory Factor-2/genetics , Lipopolysaccharides/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Plasma Cells/transplantation , Positive Regulatory Domain I-Binding Factor 1 , T-Lymphocytes, Helper-Inducer/immunology , Transcription Factors/genetics
15.
J Allergy Clin Immunol ; 129(4): 1048-55.e6, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22385635

ABSTRACT

BACKGROUND: The clarification of cutaneous dendritic cell subset and the role of thymic stromal lymphopoietin (TSLP) signaling in epicutaneous sensitization with protein antigens, as in the development of atopic dermatitis, is a crucial issue. OBJECTIVES: Because TSLP is highly expressed in the vicinity of Langerhans cells (LCs), we sought to clarify our hypothesis that LCs play an essential role in epicutaneous sensitization with protein antigens through TSLP signaling. METHODS: By using Langerin-diphtheria toxin receptor knock-in mice and human Langerin-diphtheria toxin A transgenic mice, we prepared mice deficient in LCs. We also prepared mice deficient in TSLP receptors in LCs by using TSLP receptor-deficient mice with bone marrow chimeric technique. We applied these mice to an ovalbumin (OVA)-induced epicutaneous sensitization model. RESULTS: Upon the epicutaneous application of OVA, conditional LC depletion attenuated the development of clinical manifestations as well as serum OVA-specific IgE increase, OVA-specific T-cell proliferation, and IL-4 mRNA expression in the draining lymph nodes. Consistently, even in the steady state, permanent LC depletion resulted in decreased serum IgE levels, suggesting that LCs mediate the T(H)2 local environment. In addition, mice deficient in TSLP receptors on LCs abrogated the induction of OVA-specific IgE levels upon epicutaneous OVA sensitization. CONCLUSION: LCs initiate epicutaneous sensitization with protein antigens and induce T(H)2-type immune responses via TSLP signaling.


Subject(s)
Allergens/immunology , Dermatitis, Allergic Contact/immunology , Langerhans Cells/immunology , Ovalbumin/immunology , Receptors, Cytokine/metabolism , Signal Transduction , Administration, Cutaneous , Allergens/administration & dosage , Animals , Bone Marrow Cells/metabolism , Chemokines/biosynthesis , Chimerism , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Dermatitis, Allergic Contact/metabolism , Disease Models, Animal , Epitopes , Female , Immunoglobulin E/blood , Immunoglobulin E/immunology , Langerhans Cells/metabolism , Lymphocyte Activation/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , OX40 Ligand/metabolism , Ovalbumin/administration & dosage , Receptors, Cytokine/genetics , Th2 Cells/immunology , Up-Regulation/immunology , Thymic Stromal Lymphopoietin
16.
Infect Immun ; 80(5): 1699-706, 2012 May.
Article in English | MEDLINE | ID: mdl-22331432

ABSTRACT

C-type lectin SIGNR1 directly recognizes Candida albicans and zymosan and has been considered to share properties of polysaccharide recognition with human DC-SIGN (hDC-SIGN). However, the precise specificity of SIGNR1 and the difference from that of hDC-SIGN remain to be elucidated. We prepared soluble forms of SIGNR1 and hDC-SIGN and conducted experiments to examine their respective specificities. Soluble SIGNR1 (sSIGNR1) bound several types of live C. albicans clinical isolate strains in an EDTA-sensitive manner. Inhibition analyses of sSIGNR1 binding by glycans from various yeast strains demonstrated that SIGNR1 preferentially recognizes N-glycan α-mannose side chains in Candida mannoproteins, as reported in hDC-SIGN. Unlike shDC-SIGN, however, sSIGNR1 recognized not only Saccharomyces cerevisiae, but also C. albicans J-1012 glycan, even after α-mannosidase treatment that leaves only ß1,2-mannose-capped α-mannose side chains. In addition, glycomicroarray analyses showed that sSIGNR1 binds mannans from C. albicans and S. cerevisiae but does not recognize Lewis(a/b/x/y) antigen polysaccharides as in shDC-SIGN. Consistent with these results, RAW264.7 cells expressing hDC-SIGN in which the carbohydrate recognition domain (CRD) was replaced with that of SIGNR1 (RAW-chimera) produced comparable amounts of interleukin 10 (IL-10) in response to glycans from C. albicans and S. cerevisiae, but those expressing hDC-SIGN produced less IL-10 in response to S. cerevisiae than C. albicans. Furthermore, RAW-hDC-SIGN cells remarkably reduced IL-10 production after α-mannosidase treatment compared with RAW-chimera cells. These results indicate that SIGNR1 recognizes C. albicans/yeast through a specificity partly distinct from that of its homologue hDC-SIGN.


Subject(s)
Candida albicans/immunology , Candida albicans/metabolism , Cell Adhesion Molecules/metabolism , Lectins, C-Type/metabolism , Polysaccharides/metabolism , Receptors, Cell Surface/metabolism , Animals , Gene Expression Regulation , HEK293 Cells , Humans , Interleukin-10/genetics , Interleukin-10/metabolism , Macrophages , Mice , Polysaccharides/chemistry , Protein Binding , Recombinant Proteins , Saccharomyces cerevisiae
17.
Int Immunol ; 24(2): 129-36, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22247226

ABSTRACT

Sulfatide-reactive type II NKT cells, the so-called non-invariant NKT (non-iNKT) cells, have been shown to counteract invariant NKT (iNKT) cell activity. However, the effects of sulfatide on activation of iNKT cells by α-galactocylceramide (αGC) in the context of CD1d have not been studied in detail. Therefore, we studied the blocking effect of sulfatide on αGC-induced iNKT cell activation by dendritic cells (DCs). Even in the absence of non-iNKT cells, sulfatide inhibited αGC-mediated iNKT cell activation by reducing αGC/CD1d complex formations in a dose-dependent manner. This was also confirmed in a cell-free setting using immobilized CD1d-Ig. Moreover, simultaneous injection of αGC with sulfatide decreased αGC/CD1d complex formations on DCs, accompanied by the reduced CD40L-up-regulation and IFN-γ production by iNKT cells and IL-12p70 production by DCs. However, sulfatide by itself did not interfere with the presentation of MHC class II-mediated antigen presentation to specific T cells. These results demonstrate that sulfatide competes with αGC to be loaded onto CD1d along the endocytic pathway in DCs, thereby inhibiting the iNKT cell response.


Subject(s)
Antigen Presentation , Dendritic Cells/drug effects , Galactosylceramides/metabolism , Natural Killer T-Cells/metabolism , Sulfoglycosphingolipids/pharmacology , Animals , Antigen Presentation/drug effects , Antigens, CD1/metabolism , CD40 Ligand/genetics , CD40 Ligand/metabolism , Cells, Cultured , Dendritic Cells/immunology , Dendritic Cells/metabolism , Dendritic Cells/pathology , Immunosuppression Therapy , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-12/genetics , Interleukin-12/metabolism , Lymphocyte Activation/drug effects , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Natural Killer T-Cells/immunology , Natural Killer T-Cells/pathology , Protein Binding/drug effects , Up-Regulation/drug effects
19.
Int Immunol ; 24(2): 89-96, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22207132

ABSTRACT

SIGNR1, a mouse C-type lectin, binds various pathogens, including Candida albicans. In this study, we explore the impact of SIGNR1 in the recognition of C. albicans/zymosan and the subsequent tumor necrosis factor (TNF)-α production using SIGNR1-transfected RAW264.7 (RAW-SIGNR1) cells and resident peritoneal macrophages. Compared with RAW-control cells, RAW-SIGNR1 cells dramatically enhanced TNF-α production upon the stimulation with heat-killed C. albicans and zymosan. Recognition of microbes via carbohydrate recognition domain (CRD) of SIGNR1 was crucial for the enhanced TNF-α production. Consistently, such an enhancement was significantly decreased by anti-SIGNR1 mAb. Laminarin, antagonistic Dectin-1 ligand, cooperated to further diminish the response, although no effect was observed by itself in RAW-SIGNR1 cells. However, it moderately reduced the response of RAW-control cells. Zymosan depleted of toll-like receptor (TLR) ligands decreased the response, even though it was recognized by SIGNR1 and Dectin-1. Moreover, antagonistic anti-TLR2 abolished the response, suggesting that TNF-α production largely relies on TLR2-mediated signaling. Resident peritoneal macrophages expressing SIGNR1 predominantly captured zymosan injected intra-peritoneally and produced TNF-α, which was dependent on TLR2 and partly inhibited by anti-SIGNR1 mAb. Finally, physical association of SIGNR1 with the extracellular portion of TLR2 through CRD was confirmed by immunoprecipitation using various deletion mutants. These results suggest that SIGNR1 recognizing microbes participates in the enhanced TNF-α production by Mϕ in cooperation with TLR2.


Subject(s)
Candida albicans/immunology , Cell Adhesion Molecules/metabolism , Lectins, C-Type/metabolism , Macrophages, Peritoneal/metabolism , Receptors, Cell Surface/metabolism , Toll-Like Receptor 2/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Antigens, Bacterial/immunology , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/immunology , Cell Line , Host-Pathogen Interactions/drug effects , Lectins, C-Type/genetics , Lectins, C-Type/immunology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/pathology , Mice , Mice, Inbred BALB C , Mice, Knockout , Receptors, Cell Surface/genetics , Receptors, Cell Surface/immunology , Signal Transduction/immunology , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/immunology , Transgenes/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Up-Regulation/drug effects , Zymosan/administration & dosage , Zymosan/immunology
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