A novel regulatory role of gp49B on dendritic cells in T‐cell priming

Kasai, S.; Inui, Makoto; Nakamura, Kyohei; Kakizaki, Yuta; Endo, Shota; Nakamura, Akira; Ito, Sadayoshi; Takai, Toshiyuki

doi:10.1002/eji.200737550

Cited by 20 publications

(19 citation statements)

References 57 publications

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“…It has been reported that BMDCs pulsed with OVA or OVA-LPS transfer Ag sensitization to naïve mice (33,34), that BMDCs express LILRB4, and that the absence of this receptor on these culture-derived cells results in greater activation of T cells in vitro (25). We therefore cultured bone marrow cells from Lilrb4 +/+ and Lilrb4 −/− mice in GM-CSF to generate BMDCs (27).…”

Section: Resultsmentioning

confidence: 99%

“…Given that LILRB4 counterregulates LPS-mediated inflammation in several neutrophil-dependent acute effector phase models (3-5), we considered the possibility that LILRB4 might also counterregulate the development of the LPS-dependent, adaptive Th2 response to inhaled OVA through expression on DCs (25). We report here that expression of LILRB4 was strikingly upregulated on DCs bearing OVA and high levels of MHC class II and CD86 in the lung-draining lymph nodes of mice after inhalation of OVA and low-dose LPS.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Th2 Adaptive Immune Responses and Pulmonary Inflammation by Leukocyte Ig-Like Receptor B4 on Dendritic Cells

Breslow

Rao

Xing

et al. 2009

The Journal of Immunology

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We previously established that the inhibitory receptor LILRB4 mitigates LPS-induced, neutrophil-dependent pathologic effector mechanisms in inflammation. We now report that LILRB4 on dendritic cells (DCs) counterregulates development of an adaptive Th2 immune response and ensuing inflammation in a model of allergic pulmonary inflammation, initiated by inhalation sensitization with OVA and LPS followed by airway challenge with OVA. We found that Lilrb4−/− mice had significantly exacerbated eosinophilic pulmonary inflammation, as assessed in bronchoalveolar lavage and lung tissue, as well as elevated levels of OVA-specific IgE and Th2 cytokines produced by OVA-restimulated lymph node cells. LILRB4 was preferentially expressed on MHC class IIhighCD86high OVA-bearing DCs in lung-draining lymph nodes after sensitization or challenge. Moreover, the lymph nodes of Lilrb4−/− mice had significantly more of these mature DCs after challenge with OVA, which was accompanied by significantly more IL-4–producing lymphocytes, compared with Lilrb4+/+ mice. Sensitization of naive Lilrb4+/+ mice by transfer of OVA-LPS-pulsed Lilrb4−/− bone marrow-derived DCs was sufficient to confer exacerbated allergic lung pathology upon challenge with OVA, compared with mice that received Lilrb4+/+ bone marrow-derived DCs. Our findings establish that maturation and migration of pulmonary DCs to lymph nodes in response to Ag and an innate immune stimulus is associated with upregulated expression of LILRB4. In addition, this receptor attenuates the number of these mature DCs and attendant IL-4–producing lymphocytes in the lymph nodes, and accordingly, the ability of DCs to elicit pathologic Th2 pulmonary inflammation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Th2 Adaptive Immune Responses and Pulmonary Inflammation by Leukocyte Ig-Like Receptor B4 on Dendritic Cells

Breslow

Rao

Xing

et al. 2009

The Journal of Immunology

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“…TREM2 is a key regulator in chronic inflammation by stimulating the production of constitutive inflammatory cytokines (73). GP49B is a member of the immunoglobulin superfamily and has a regulatory role in T-cell priming (36). CCL9 is an interferon-␥-inducible ␤-chemokine and has shown potent antitumor activity through attraction of cytotoxic T lymphocytes and inhibition of angiogenesis (32,56).…”

Section: Discussionmentioning

confidence: 99%

Mammary gland morphological and gene expression changes underlying pregnancy protection of breast cancer tumorigenesis

Misra¹,

Bentley²,

Bond³

et al. 2012

Physiological Genomics

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A full-term pregnancy early in life reduces lifetime risk of developing breast cancer, and the effect can be mimicked in rodents by full-term pregnancy or shortterm treatment with exogenous estrogen and progesterone. To gain insight into the protective mechanism, 15 3-mo-old postpubertal virgin Lewis rats were randomly assigned to three groups: control (C), pregnancy (P), or hormone (H). The P group animals underwent a full-term pregnancy, and H group animals were implanted subcutaneously with silastic capsules filled with ethynyl estradiol and megesterol acetate for 21 days. C and P animals were implanted with sham capsules. On day 21 capsules were removed, which was followed by a 49-day involution period, euthanasia, and mammary tissue collection. Global gene expression was measured using Rat Genome 230.2 Arrays. Histological analysis revealed that P and H treatments induced sustained morphological changes in the mammary gland with significantly increased percentages of mammary parenchyma and stromal tissues and higher ratio of stroma to parenchyma. Transcriptome analysis showed that P and H treatments induced sustained global changes in gene expression in the mammary gland. Analysis of commonly up-and downregulated genes in P and H relative to C treatment showed increased expression of three matrix metallopeptidases (Mmp3, 8, and 12), more differentiated mammary phenotype, enhanced innate and adaptive immunity, and reduced cell proliferation and angiogenic signatures. The sustained morphological and global gene expression changes in mammary tissue after pregnancy and hormone treatment may function together to provide the protective effect against breast cancer. breast cancer protection; hormone; pregnancy BREAST CANCER IS ONE OF THE most common cancers in women and affects nearly 10% of all women in US. In the year 2009, 192,370 new cases of invasive and 62,280 new cases of in situ breast cancer were estimated to have occurred, with 40,170 estimated deaths (3). Various epidemiological studies have revealed that multiple factors including hormones, genetics, reproductive history, radiation, socio-economic status, place of residence, ethnicity, and the environment affect the incidence of breast cancer (9,19,28,29,50,51,60). It has been shown that full-term pregnancy early in life has a protective effect on women against the risk of breast cancer irrespective of genetic background, age, race, or ethnic background (2,37,39,40,64,65,72). For instance, Lambe et al. (1996) (39, 40) and Albrektsen et al. (2005) (2) reported that full-term gestation in a woman younger than 24 yr of age reduces her lifetime risk of developing breast cancer, and this parity-induced protection against breast cancer is significantly affected by the total number of pregnancies. The epidemiological data on breastfeeding and breast cancer risk in humans also show that prolonged breast-feeding confers additional protection against breast cancer (17). However, aborted pregnancies are not associated with decreased risk for breast cancer (8).A ...

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“…Although three strains of gp49B-null knockout mice have been published, so far profiles of B cell subsets have not been reported in any of these mice (37,44,45). Therefore, we analyzed B cell subsets in lymphoid organs by flow cytometry.…”

Section: Gp49b Is Selectively Expressed On Memory and Mz B Cellsmentioning

confidence: 99%

gp49B-Mediated Negative Regulation of Antibody Production by Memory and Marginal Zone B Cells

Fukao

Haniuda

Nojima

et al. 2014

The Journal of Immunology

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The rapid Ab responses observed after primary and secondary immunizations are mainly derived from marginal zone (MZ) and memory B cells, respectively, but it is largely unknown how these responses are negatively regulated. Several inhibitory receptors have been identified and their roles have been studied, but mainly on follicular B cells and much less so on MZ B, and never on memory B cells. gp49B is an Ig superfamily member that contains two ITIMs in its cytoplasmic tail, and it has been shown to negatively regulate mast cell, macrophage, and NK cell responses. In this study, we demonstrate that gp49B is preferentially expressed on memory and MZ B cells. We show that gp49B−/− mice produce more IgM after a primary immunization and more IgM and IgG1 after a secondary immunization than gp49B+/+ mice in T cell–dependent immune responses. Memory and MZ B cells from gp49B−/− mice also produce more Abs upon in vitro stimulation with CD40 than those from gp49B+/+ mice. The in vitro IgM production by MZ B cells from gp49B+/+, but not gp49B−/−, mice is suppressed by interaction with a putative gp49B ligand, the integrin αvβ3 heterodimer. In addition, gp49B−/− mice exhibited exaggerated IgE production in the memory recall response. These results suggest that plasma cell development from memory and MZ B cells, as well as subsequent Ab production, are suppressed via gp49B. In memory B cells, this suppression also prevents excessive IgE production, thus curtailing allergic diseases.

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A novel regulatory role of gp49B on dendritic cells in T‐cell priming

Cited by 20 publications

References 57 publications

Inhibition of Th2 Adaptive Immune Responses and Pulmonary Inflammation by Leukocyte Ig-Like Receptor B4 on Dendritic Cells

Inhibition of Th2 Adaptive Immune Responses and Pulmonary Inflammation by Leukocyte Ig-Like Receptor B4 on Dendritic Cells

Mammary gland morphological and gene expression changes underlying pregnancy protection of breast cancer tumorigenesis

gp49B-Mediated Negative Regulation of Antibody Production by Memory and Marginal Zone B Cells

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