Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit anti-tumor and anti-infection immunity. Here, we report that Hsp70-like protein 1 (Hsp70L1), a novel HSP derived from human dendritic cel...Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit anti-tumor and anti-infection immunity. Here, we report that Hsp70-like protein 1 (Hsp70L1), a novel HSP derived from human dendritic cells (DCs), has potent adjuvant effects that polarize responses toward Th1. With a calculated molecular weight of 54.8 kDa, Hsp70L1 is smaller in size than Hsp70 but resembles it both structurally and functionally. Hsp70L1 shares common receptors on DCs with Hsp70 and can interact with DCs, promoting DC maturation and stimulating secretion of the proinflammatory cytokines interleukin 12p70 (IL-12p70), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), and the chemokines IP-10, macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and normal T cell expressed and secreted (RANTES). The induction of interferon-gamma-inducible protein 10 (IP-10) secretion by Hsp70L1 is not shared by Hsp70, and other functional differences include more potent stimulation of DC IL-12p70, CC-chemokine, and CCR7 and CXCR4 expression by Hsp70L1. Immunization of mice with the hybrid peptide Hsp70L1-ovalbumin(OVA)(257-264) induces an OVA(257-264)-specific Th1 response and cytotoxic T lymphocyte (CTL) that results in significant inhibition of E.G7-OVA tumor growth. The ability of Hsp70L1 to activate DCs indicates its potential as a novel adjuvant for use with peptide immunizations; the Hsp70L1 antigen peptide hybrid may serve as a more effective vaccine for the control of cancer and infectious diseases.展开更多
OBJECTIVE Ginsenoside metabolite compound K(CK)is a degradation product of ginsenoside in the intestine by bacteria.The anti-inflammatory and immunomodulatory activities of CK have been reported.This study investigate...OBJECTIVE Ginsenoside metabolite compound K(CK)is a degradation product of ginsenoside in the intestine by bacteria.The anti-inflammatory and immunomodulatory activities of CK have been reported.This study investigated whether CK exerted its immunoregulatory effect through modulation of dendritic cells(DCs)function.METHODS In vivo,severity of collegen-induced arthritis(CIA),T cells and DCs subsets,phenotype of DC were assayed by flow cytometry,CCL19 and CCL21 level in lymph nodes assayed by ELISA.In vitro,bone marrow-derived DCs from normal mice were matured with lipopolysaccharide and treated with CK for 48 h.In vivo,bone marrow-derived DCs were generated from CIA mice before and 2 weeks into CK treatment.DCs were analyzed for migration,phenotype and T-cell stimulatory capacity.RESULTS CK alleviated the severity of CIA,decreased pD Cs and mo-DCs,increased na?ve T cells in CIA mice lymph nodes,and suppressed CCL21 expression in lymph nodes.CK suppressed DCs migration induced by CCL21 and T cells-stimulatory capability of DC,down-regulated LPS-induced expression of CD80,CD86,MHCII and CCR7 on DCs.CONCLUSION This study elucidated the novel immunomodulatory property of CK via impairing function of DCs in priming T cells activation.These results provide an interesting novel insight into the potential mechanism by which CK contribute to the restoration of immunoregulation in autoimmune conditions.展开更多
Dendritic cells （DCs） are bone marrow-derived professional antigen presenting cells （APCs）, they are crucial for initiation of both innate and adaptive immune responses. In this study, chicken bone marrow （chBM）...Dendritic cells （DCs） are bone marrow-derived professional antigen presenting cells （APCs）, they are crucial for initiation of both innate and adaptive immune responses. In this study, chicken bone marrow （chBM） cells were cultured in medium with recombinant chicken granulocyte-macrophage colony stimulating factor （rGM-CSF） and recombinant chicken interleukin-4 （rIL-4） for 7 days, displayed the typical morphology of DCs. These immature chicken bone marrow-derived DCs （chBM-DCs） showed signifcant up-regulation of the putative CD11c and of major histocompatibility complex class II （MHC II）, but CD40 and CD86 co-stimulatory molecules were almost no up-regulated. However, maturation with lipopolysaccharide （LPS）, surface expression of CD40, CD86 was greatly increased. The phagocytosis of chBM-DCs was assessed by neutral red, and the phagocytosis decreased after stimulation. In mixed lymphocyte responses （MLR）, stimulated chBM-DCs were more effective to T-cell stimulators than non-stimulated chBM-DCs. In addition, mRNA expression levels of IL-1β, IL-4, IL-6, IL-10, IL-12, IFN-γ, TNF-α, CXCLi1 and CXCLi2 were assessed by real-time qPCR （qRT-PCR）, and the results showed cultured chBM-DCs could be matured to a T helper cell type 1 （Th1）-promoting phenotype by LPS stimulation.展开更多
Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migra...Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow-derived DCs toward macrophage inflammatory protein-3beta (MIP-3beta) and induces them to retain responsiveness to MIP-1alpha after lipopolysaccharide (LPS)-stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.展开更多
2025年6月16日,上海交通大学医学院附属第一人民医院王宏林团队在Immunity杂志在线发表了题为“Nociceptor-derived CGRP enhances dermal type I conventional dendritic cell function to drive autoreactive CD8+T cell responses in...2025年6月16日,上海交通大学医学院附属第一人民医院王宏林团队在Immunity杂志在线发表了题为“Nociceptor-derived CGRP enhances dermal type I conventional dendritic cell function to drive autoreactive CD8+T cell responses in vitiligo”的研究论文。该研究联合单细胞测序、空间转录组测序、皮肤全包埋透明化成像、近10种基因工程小鼠与研究者发起临床试验(investigator-initiated trial,IIT),揭示了白癜风中存在“感觉神经元-CGRP-cDC1-CD8^(+)T细胞”致病新机制;通过CGRP受体拮抗剂(rimegepant)阻断该神经-免疫互作轴,显著抑制了白癜风模型小鼠的疾病进展,并在57例白癜风患者的临床试验中展现出良好的治疗效果。该研究为白癜风治疗策略研发提供了新的理论依据和靶标,并形成了完整的“临床-基础-临床”的研究环路。展开更多
文摘Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit anti-tumor and anti-infection immunity. Here, we report that Hsp70-like protein 1 (Hsp70L1), a novel HSP derived from human dendritic cells (DCs), has potent adjuvant effects that polarize responses toward Th1. With a calculated molecular weight of 54.8 kDa, Hsp70L1 is smaller in size than Hsp70 but resembles it both structurally and functionally. Hsp70L1 shares common receptors on DCs with Hsp70 and can interact with DCs, promoting DC maturation and stimulating secretion of the proinflammatory cytokines interleukin 12p70 (IL-12p70), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), and the chemokines IP-10, macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and normal T cell expressed and secreted (RANTES). The induction of interferon-gamma-inducible protein 10 (IP-10) secretion by Hsp70L1 is not shared by Hsp70, and other functional differences include more potent stimulation of DC IL-12p70, CC-chemokine, and CCR7 and CXCR4 expression by Hsp70L1. Immunization of mice with the hybrid peptide Hsp70L1-ovalbumin(OVA)(257-264) induces an OVA(257-264)-specific Th1 response and cytotoxic T lymphocyte (CTL) that results in significant inhibition of E.G7-OVA tumor growth. The ability of Hsp70L1 to activate DCs indicates its potential as a novel adjuvant for use with peptide immunizations; the Hsp70L1 antigen peptide hybrid may serve as a more effective vaccine for the control of cancer and infectious diseases.
基金supported by National Nature Science Foundation of China(81503084,81330081,31200675,and 81173075)
文摘OBJECTIVE Ginsenoside metabolite compound K(CK)is a degradation product of ginsenoside in the intestine by bacteria.The anti-inflammatory and immunomodulatory activities of CK have been reported.This study investigated whether CK exerted its immunoregulatory effect through modulation of dendritic cells(DCs)function.METHODS In vivo,severity of collegen-induced arthritis(CIA),T cells and DCs subsets,phenotype of DC were assayed by flow cytometry,CCL19 and CCL21 level in lymph nodes assayed by ELISA.In vitro,bone marrow-derived DCs from normal mice were matured with lipopolysaccharide and treated with CK for 48 h.In vivo,bone marrow-derived DCs were generated from CIA mice before and 2 weeks into CK treatment.DCs were analyzed for migration,phenotype and T-cell stimulatory capacity.RESULTS CK alleviated the severity of CIA,decreased pD Cs and mo-DCs,increased na?ve T cells in CIA mice lymph nodes,and suppressed CCL21 expression in lymph nodes.CK suppressed DCs migration induced by CCL21 and T cells-stimulatory capability of DC,down-regulated LPS-induced expression of CD80,CD86,MHCII and CCR7 on DCs.CONCLUSION This study elucidated the novel immunomodulatory property of CK via impairing function of DCs in priming T cells activation.These results provide an interesting novel insight into the potential mechanism by which CK contribute to the restoration of immunoregulation in autoimmune conditions.
基金Supported by the National Technology and Research Project(2015BAD12B01-4)
文摘Dendritic cells （DCs） are bone marrow-derived professional antigen presenting cells （APCs）, they are crucial for initiation of both innate and adaptive immune responses. In this study, chicken bone marrow （chBM） cells were cultured in medium with recombinant chicken granulocyte-macrophage colony stimulating factor （rGM-CSF） and recombinant chicken interleukin-4 （rIL-4） for 7 days, displayed the typical morphology of DCs. These immature chicken bone marrow-derived DCs （chBM-DCs） showed signifcant up-regulation of the putative CD11c and of major histocompatibility complex class II （MHC II）, but CD40 and CD86 co-stimulatory molecules were almost no up-regulated. However, maturation with lipopolysaccharide （LPS）, surface expression of CD40, CD86 was greatly increased. The phagocytosis of chBM-DCs was assessed by neutral red, and the phagocytosis decreased after stimulation. In mixed lymphocyte responses （MLR）, stimulated chBM-DCs were more effective to T-cell stimulators than non-stimulated chBM-DCs. In addition, mRNA expression levels of IL-1β, IL-4, IL-6, IL-10, IL-12, IFN-γ, TNF-α, CXCLi1 and CXCLi2 were assessed by real-time qPCR （qRT-PCR）, and the results showed cultured chBM-DCs could be matured to a T helper cell type 1 （Th1）-promoting phenotype by LPS stimulation.
文摘Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow-derived DCs toward macrophage inflammatory protein-3beta (MIP-3beta) and induces them to retain responsiveness to MIP-1alpha after lipopolysaccharide (LPS)-stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.
文摘2025年6月16日,上海交通大学医学院附属第一人民医院王宏林团队在Immunity杂志在线发表了题为“Nociceptor-derived CGRP enhances dermal type I conventional dendritic cell function to drive autoreactive CD8+T cell responses in vitiligo”的研究论文。该研究联合单细胞测序、空间转录组测序、皮肤全包埋透明化成像、近10种基因工程小鼠与研究者发起临床试验(investigator-initiated trial,IIT),揭示了白癜风中存在“感觉神经元-CGRP-cDC1-CD8^(+)T细胞”致病新机制;通过CGRP受体拮抗剂(rimegepant)阻断该神经-免疫互作轴,显著抑制了白癜风模型小鼠的疾病进展,并在57例白癜风患者的临床试验中展现出良好的治疗效果。该研究为白癜风治疗策略研发提供了新的理论依据和靶标,并形成了完整的“临床-基础-临床”的研究环路。
