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
Heat-shock protein(HSP)-based immunotherapy is established on its adjuvant effects when applied via an extracellular approach to pulse and activate dendritic cells(DCs).Our previous studies indicate that DCs pulsed wi...Heat-shock protein(HSP)-based immunotherapy is established on its adjuvant effects when applied via an extracellular approach to pulse and activate dendritic cells(DCs).Our previous studies indicate that DCs pulsed with recombinant fusion proteins of antigenic fragment and HSP70-like protein 1(HSP70L1)are potent in stimulating antigen-specific Th1 responses.We herein evaluated the cytotoxic T cell(CTL)response by an intracellular approach of priming DCs with transfection of recombinant adenovirus-expressing the fusion gene of the 576–699 fragment of carcinoembryonic antigen(CEA)and HSP70L1.As compared with DCs pulsed with extracellular fusion protein,the DCs transfected with recombinant adenovirus expressing the fusion gene displayed equivalent mature phenotypes but less inflammatory appearance.However,the transfected DCs were superior to the pulsed DCs in inducing CEA-specific CTLs.Consistently,immunization of HLA-A2.1/H-2Kb transgene mice with the transfected DCs could induce more quantities of HLA-A2.1-restricted CEA-specific CTLs,protecting nude mice more significantly from human CEA-expressing colon tumor challenge when adoptively transferred.Mechanistic investigation indicated that intracellular expression of the fusion protein empowered the transfected DCs by activation of STAT1 possibly via inducing IFN-βand ERK pathways.Therefore,the more potent ability to induce anti-CEA CTL responses enables the DCs,which transfected with recombinant adenovirus expressing the fusion gene of antigenic CEA fragment and Th1 adjuvant,as an alternative promising approach for the immunotherapy of CEA-positive tumors.展开更多
Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and developm...Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and development remain poorly understood.Our previous studies show that extracellular heat shock protein 70-like protein(HSP70L1)is a potent adjuvant of Th1 responses via stimulating DCs when released from cells;however,the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown.Herein,we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression,in contrast to the adjuvant activity of extracellular HSP70L1.The stability of intracellular HSP70L1 is dependent on DNAJC2,a known epigenetic regulator.Mechanistically,intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory,MHC and STAT3 genes.Thus,intracellular HSP70L1 is an inhibitor of human DC maturation.Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.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We thank Drs Chaofeng Han,Meng Xia and Kun Chen for technical assistanceThis work was supported by grants from the National High-Tech Projects(2012AA020808 and 2007AA021003).
文摘Heat-shock protein(HSP)-based immunotherapy is established on its adjuvant effects when applied via an extracellular approach to pulse and activate dendritic cells(DCs).Our previous studies indicate that DCs pulsed with recombinant fusion proteins of antigenic fragment and HSP70-like protein 1(HSP70L1)are potent in stimulating antigen-specific Th1 responses.We herein evaluated the cytotoxic T cell(CTL)response by an intracellular approach of priming DCs with transfection of recombinant adenovirus-expressing the fusion gene of the 576–699 fragment of carcinoembryonic antigen(CEA)and HSP70L1.As compared with DCs pulsed with extracellular fusion protein,the DCs transfected with recombinant adenovirus expressing the fusion gene displayed equivalent mature phenotypes but less inflammatory appearance.However,the transfected DCs were superior to the pulsed DCs in inducing CEA-specific CTLs.Consistently,immunization of HLA-A2.1/H-2Kb transgene mice with the transfected DCs could induce more quantities of HLA-A2.1-restricted CEA-specific CTLs,protecting nude mice more significantly from human CEA-expressing colon tumor challenge when adoptively transferred.Mechanistic investigation indicated that intracellular expression of the fusion protein empowered the transfected DCs by activation of STAT1 possibly via inducing IFN-βand ERK pathways.Therefore,the more potent ability to induce anti-CEA CTL responses enables the DCs,which transfected with recombinant adenovirus expressing the fusion gene of antigenic CEA fragment and Th1 adjuvant,as an alternative promising approach for the immunotherapy of CEA-positive tumors.
基金We thank Yanfeng Li for the technical assistance.This work was supported by grants from the National Key R&D Program of China(2018YFA0507401)the National Natural Science Foundation of China(31670875 and 31470858).
文摘Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and development remain poorly understood.Our previous studies show that extracellular heat shock protein 70-like protein(HSP70L1)is a potent adjuvant of Th1 responses via stimulating DCs when released from cells;however,the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown.Herein,we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression,in contrast to the adjuvant activity of extracellular HSP70L1.The stability of intracellular HSP70L1 is dependent on DNAJC2,a known epigenetic regulator.Mechanistically,intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory,MHC and STAT3 genes.Thus,intracellular HSP70L1 is an inhibitor of human DC maturation.Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.
