Traditionally,macroautophagy(autophagy)is viewed as a pathway of cell survival.Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods o...Traditionally,macroautophagy(autophagy)is viewed as a pathway of cell survival.Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods of stress.Interestingly,autophagy can also directly intersect with,and impact,other major pathways of cellular function.Here,we will review the contribution of autophagy to pathways of antigen presentation.The autophagy machinery acts to modulate both MHCⅠ and MHCⅡ antigen presentation.As such autophagy is an important participant in pathways that elicit host cell immunity and the elimination of infectious pathogens.展开更多
The liver is an important immunological organ that controls systemic tolerance.The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance.Orches...The liver is an important immunological organ that controls systemic tolerance.The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance.Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment,which Is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes.In response to pathogens or autoantigens,tolerance is disrupted by unknown mechanisms.Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties.The presentation of microbial and endogenous lipid-,metabolite-and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance.Perturbation of this balance results in autoimmune liver diseases,such as autoimmune hepatitis,primary biliary cholangitis,and primary sclerosing cholangitis.Although the exact etiologies of these autoimmune liver diseases are unknown,it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids,as well as alterations in bile acid composition,may result in changes in effector cell activation and polarization and may reduce or impair protective antiinflammatory regulatory T and B cell responses.Additionally,the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different(non)immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance.Here,we summarize emerging aspects of antigen presentation,autoantibody production,and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.展开更多
Activating humoral and cellular immunity in lymph nodes(LNs)of nanoparticle-based vaccines is critical to controlling tumors.However,how the physical properties of nanovaccine carriers orchestrate antigen capture,lymp...Activating humoral and cellular immunity in lymph nodes(LNs)of nanoparticle-based vaccines is critical to controlling tumors.However,how the physical properties of nanovaccine carriers orchestrate antigen capture,lymphatic delivery,antigen presentation and immune response in LNs is largely unclear.Here,we manufactured gold nanoparticles(AuNPs)with the same size but different shapes(cages,rods,and stars),and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas.Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes.On lymphatic delivery,both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention.A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity,which is mediated by CD4^(+)T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study.Interestingly,cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8^(+)T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study.These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs,and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.展开更多
The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurre...The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurrence and development of Parkinson’s disease.However,it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I pathway.In the present study,polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium(MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease mouse model.The findings revealed that MHC-I was expressed in both models.To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells,immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8(CD8)+T cell infiltration in the substantia nigra of MPTP-treated mice.The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+T cells.Moreover,in MPTP-induced Parkinson’s disease model mice,the genetic knockdown of endogenous MHC-I,which was caused by injecting specific adenovirus into the substantia nigra,led to a significant reduction in CD8+T cell infiltration and alleviated dopaminergic neuronal death.To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation,the expression of PTEN-induced kinase 1(PINK1)was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA(siRNA),and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells.Taken together,MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation,thus rendering dopaminergic neurons susceptible to immune cells and degeneration.This may be one of the mechanisms of oxidative stress-induced Parkinson’s disease,and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation.All animal experiments were approved by the Southern Medical University Ethics Committee(No.81802040,approved on February 25,2018).展开更多
The role of the p38 signaling pathway in the innate and adaptive immune responses has been well documented,especially in inflammatory cytokine production by dendritic cells(DCs).However,whether the p38 signaling pathw...The role of the p38 signaling pathway in the innate and adaptive immune responses has been well documented,especially in inflammatory cytokine production by dendritic cells(DCs).However,whether the p38 signaling pathway affects the important antigen(Ag)presentation function of DCs remains largely unknown.In this study,we reported that the deletion of p38αresulted in an impaired cross-presentation ability of CD8^(+) conventional DCs(cDCs)and a reduction in the direct presentation ability of CD8−cDCs ex vivo.Further study revealed that p38αhad a crucial role in Ag processing by CD8^(+) cDCs but did not affect the Ag uptake or co-stimulation of T cells.Moreover,p38αdeficiency led to reduced cross-priming of T cells in vivo.The production of the IL-12p40 and IL-12p70 cytokines by p38α-deficient cDCs was also significantly reduced.Our study identified a new role for p38αin modulating the important antigen cross-presentation function of DCs.展开更多
Antigen-presentation via major histocompatibility complex(MHC)to T cells is the key event to initiate adaptive immune responses.In teleosts,as in mammals,the main types of professional antigen-presenting cells(APCs)ar...Antigen-presentation via major histocompatibility complex(MHC)to T cells is the key event to initiate adaptive immune responses.In teleosts,as in mammals,the main types of professional antigen-presenting cells(APCs)are dendritic cells(DCs),monocytes/macrophages,and B cells.In the current study,flow cytometry,immunostaining and qPCR have been used to show that neutrophils in the teleost fish Atlantic salmon(Salmo salar L.)have antigen-presenting properties.The neutrophils were positive for MHC class II,CD83 and CD80/86,and upon in vitro bacterial exposure,gene expression analysis of purified neutrophils showed that IL-12p40,which is essential for proliferation of naïve T cells,was highly upregulated at both 6 and 24 h post bacterial exposure.Based on presence of MHC class II and upregulation of molecules involved in antigen presentation and T cell activation,we suggest that neutrophils in Atlantic salmon have potential to function as professional APCs.This work makes an important basis for further exploring the potential of using neutrophils to develop new,targeted immunoprophylactic measures.展开更多
Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines.To date,only a few adjuvants have been approved for use in humans,among which aluminum-con...Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines.To date,only a few adjuvants have been approved for use in humans,among which aluminum-containing adjuvants are the only ones widely used.However,the medical need for potent and safe adjuvants is currently continuously increasing,especially those triggering cellular immune responses for cytotoxic T lymphocyte activation,which are urgently needed for the development of efficient virus and cancer vaccines.Manganese is an essential micronutrient required for diverse biological activities,but its functions in immunity remain undefined.We previously reported that Mn^(2+) is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn^(2+)alone directly activates cGAS independent of dsDNA,leading to an unconventional catalytic synthesis of 2′3′-cGAMP.Herein,we found that Mn^(2+) strongly promoted immune responses by facilitating antigen uptake,presentation,and germinal center formation via both cGAS-STING and NLRP3 activation.Accordingly,a colloidal manganese salt(Mn jelly,MnJ)was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses,inducing antibody production and CD4^(+)/CD8^(+)T-cell proliferation and activation by either intramuscular or intranasal immunization.When administered intranasally,MnJ also worked as a mucosal adjuvant,inducing high levels of secretory IgA.MnJ showed good adjuvant effects for all tested antigens,including T cell-dependent and T cell-independent antigens,such as bacterial capsular polysaccharides,thus indicating that it is a promising adjuvant candidate.展开更多
Stimulator of interferon genes(STING) is a cytosolic DNA sensor which is regarded as a potential target for antitumor immunotherapy. However, clinical trials of STING agonists display limited anti-tumor effects and do...Stimulator of interferon genes(STING) is a cytosolic DNA sensor which is regarded as a potential target for antitumor immunotherapy. However, clinical trials of STING agonists display limited anti-tumor effects and dose-dependent side-effects like inflammatory damage and cell toxicity. Here,we showed that tetrahedral DNA nanostructures(TDNs) actively enter macrophages to promote STING activation and M1 polarization in a size-dependent manner, and synergized with Mn^(2+) to enhance the expressions of IFN-β and iNOS, as well as the co-stimulatory molecules for antigen presentation. Moreover, to reduce the cytotoxicity of Mn^(2+),we constructed a TDN-MnO_(2) complex and found that it displayed a much higher efficacy than TDN plus Mn^(2+) to initiate macrophage activation and anti-tumor response both in vitro and in vivo. Together, our studies explored a novel immune activation effect of TDN in cancer therapy and its synergistic therapeutic outcomes with MnO_(2).These findings provide new therapeutic opportunities for cancer therapy.展开更多
Tumor immunotherapy as a promising method for tumor treatment received tremendous attention. However, the problem of low clinical response rate still needs to be solved, especially in the poorly immunogenic tumors. Th...Tumor immunotherapy as a promising method for tumor treatment received tremendous attention. However, the problem of low clinical response rate still needs to be solved, especially in the poorly immunogenic tumors. The enhancement of tumor antigens presentation can effectively activate dendritic cells (DCs) and improve the tumor immunotherapy. In this work, TAK-243 as an inhibitor of the ubiquitin activating enzyme (UAE), was fabricated into cationic lipid-assisted nanoparticle (CLANTAK-243). The obtained CLANTAK-243 could act as an effective tumor immunotherapy enhancer to promote the maturation of DCs as well as antigen presentation, which obviously stimulated the T cells activation and proliferation. Such CLANTAK-243 injected intravenously could well trigger immune response to tumor cells in vivo. Importantly, mice treated with CLANTAK-243 could obtain a long immune memory effect to protect themselves from re-challenged tumor cells. Therefore, this work presented an effective immunotherapy strategy for poorly immunogenic tumor.展开更多
T cell recognition of foreign peptide antigen and toler-ance to self peptides is key to the proper function of the immune system.Usually,in the thymus T cells that rec-ognize self MHC+self peptides are deleted and tho...T cell recognition of foreign peptide antigen and toler-ance to self peptides is key to the proper function of the immune system.Usually,in the thymus T cells that rec-ognize self MHC+self peptides are deleted and those with the potential to recognize self MHC+foreign pep-tides are selected to mature.However there are excep-tions to these rules.Autoimmunity and allergy are two of the most common immune diseases that can be related to recognition of self.Many genes work together to lead to autoimmunity.Of those,particular MHC alleles are the most strongly associated,reflecting the key importance of MHC presentation of self peptides in autoimmunity.T cells specific for combinations of self MHC and self pep-tides may escape thymus deletion,and thus be able to drive autoimmunity,for several reasons:the relevant self peptide may be presented at low abundance in the thy-mus but at high level in particular peripheral tissues;the relevant self peptide may bind to MHC in an unusual register,not present in the thymus but apparent else-where;finally the relevant self peptide may be post translationally modified in a tissue specific fashion.In some types of allergy,the peptide+MHC combination may also be fully derived from self.However the combi-nation in question may be modified by the presence of other ligands,such as small drug molecules or metal ions.Thus these types of allergies may act like the post translationally modified peptides involved some types of autoimmunity.展开更多
Vaccination is the most effective way to prevent coronavirus disease 2019(COVID-19).Vaccine development approaches consist of viral vector vaccines,DNA vaccine,RNA vaccine,live attenuated virus,and recombinant protein...Vaccination is the most effective way to prevent coronavirus disease 2019(COVID-19).Vaccine development approaches consist of viral vector vaccines,DNA vaccine,RNA vaccine,live attenuated virus,and recombinant proteins,which elicit a specific immune response.The use of nanoparticles displaying antigen is one of the alternative approaches to conventional vaccines.This is due to the fact that nano-based vaccines are stable,able to target,form images,and offer an opportunity to enhance the immune responses.The diameters of ultrafine nanoparticles are in the range of 1–100 nm.The application of nanotechnology on vaccine design provides precise fabrication of nanomaterials with desirable properties and ability to eliminate undesirable features.To be successful,nanomaterials must be uptaken into the cell,especially into the target and able to modulate cellular functions at the subcellular levels.The advantages of nano-based vaccines are the ability to protect a cargo such as RNA,DNA,protein,or synthesis substance and have enhanced stability in a broad range of pH,ambient temperatures,and humidity for long-term storage.Moreover,nano-based vaccines can be engineered to overcome biological barriers such as nonspecific distribution in order to elicit functions in antigen presenting cells.In this review,we will summarize on the developing COVID-19 vaccine strategies and how the nanotechnology can enhance antigen presentation and strong immunogenicity using advanced technology in nanocarrier to deliver antigens.The discussion about their safe,effective,and affordable vaccines to immunize against COVID-19 will be highlighted.展开更多
基金supported by a National Health and Medical Research Council of Australia Career Development Award.
文摘Traditionally,macroautophagy(autophagy)is viewed as a pathway of cell survival.Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods of stress.Interestingly,autophagy can also directly intersect with,and impact,other major pathways of cellular function.Here,we will review the contribution of autophagy to pathways of antigen presentation.The autophagy machinery acts to modulate both MHCⅠ and MHCⅡ antigen presentation.As such autophagy is an important participant in pathways that elicit host cell immunity and the elimination of infectious pathogens.
基金supported by funding from the German Research Foundation(DFG),Collaborative Research grants within the CRC841(SFB841:"Liver inflammation:Infection,immune regulation und consequences"),projects B01 to A.K.H.and G.T.,B09 to L.D.the Clinical Research Group KF0306("Primary Sclerosing Cholangitis"),project 04 to G.T.
文摘The liver is an important immunological organ that controls systemic tolerance.The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance.Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment,which Is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes.In response to pathogens or autoantigens,tolerance is disrupted by unknown mechanisms.Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties.The presentation of microbial and endogenous lipid-,metabolite-and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance.Perturbation of this balance results in autoimmune liver diseases,such as autoimmune hepatitis,primary biliary cholangitis,and primary sclerosing cholangitis.Although the exact etiologies of these autoimmune liver diseases are unknown,it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids,as well as alterations in bile acid composition,may result in changes in effector cell activation and polarization and may reduce or impair protective antiinflammatory regulatory T and B cell responses.Additionally,the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different(non)immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance.Here,we summarize emerging aspects of antigen presentation,autoantibody production,and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.
基金supported by the National Natural Science Foundation of China(Nos.81901878,U1804183,and 82202318)Key Scientific Research Project(Education Department of Henan Province,China,20HASTIT049)China Postdoctoral Science Foundation(2019M662553,2020T130611,and 2022TQ0310)。
文摘Activating humoral and cellular immunity in lymph nodes(LNs)of nanoparticle-based vaccines is critical to controlling tumors.However,how the physical properties of nanovaccine carriers orchestrate antigen capture,lymphatic delivery,antigen presentation and immune response in LNs is largely unclear.Here,we manufactured gold nanoparticles(AuNPs)with the same size but different shapes(cages,rods,and stars),and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas.Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes.On lymphatic delivery,both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention.A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity,which is mediated by CD4^(+)T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study.Interestingly,cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8^(+)T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study.These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs,and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.
基金This work was supported by the National Natural Science Foundation of China,Nos.81671240(to SZZ),81560220(to GHL)the Youth Science Foundation of Jiangxi Province of China,No.20151BAB215014(to GHL)Health and Family Planning Commission of Jiangxi Province of China,No.20195109(to GHL)。
文摘The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurrence and development of Parkinson’s disease.However,it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I pathway.In the present study,polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium(MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease mouse model.The findings revealed that MHC-I was expressed in both models.To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells,immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8(CD8)+T cell infiltration in the substantia nigra of MPTP-treated mice.The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+T cells.Moreover,in MPTP-induced Parkinson’s disease model mice,the genetic knockdown of endogenous MHC-I,which was caused by injecting specific adenovirus into the substantia nigra,led to a significant reduction in CD8+T cell infiltration and alleviated dopaminergic neuronal death.To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation,the expression of PTEN-induced kinase 1(PINK1)was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA(siRNA),and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells.Taken together,MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation,thus rendering dopaminergic neurons susceptible to immune cells and degeneration.This may be one of the mechanisms of oxidative stress-induced Parkinson’s disease,and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation.All animal experiments were approved by the Southern Medical University Ethics Committee(No.81802040,approved on February 25,2018).
基金This work was supported by grants from the Chinese Ministry of Science and Technology National Major Scientific Research Program(2015CB943200)the Key Project Grant from the National Natural Science Foundation of China(31330027)+1 种基金the National Basic Research Program of China(2015CB553800)the Tsinghua Science Foundation(20111080963).
文摘The role of the p38 signaling pathway in the innate and adaptive immune responses has been well documented,especially in inflammatory cytokine production by dendritic cells(DCs).However,whether the p38 signaling pathway affects the important antigen(Ag)presentation function of DCs remains largely unknown.In this study,we reported that the deletion of p38αresulted in an impaired cross-presentation ability of CD8^(+) conventional DCs(cDCs)and a reduction in the direct presentation ability of CD8−cDCs ex vivo.Further study revealed that p38αhad a crucial role in Ag processing by CD8^(+) cDCs but did not affect the Ag uptake or co-stimulation of T cells.Moreover,p38αdeficiency led to reduced cross-priming of T cells in vivo.The production of the IL-12p40 and IL-12p70 cytokines by p38α-deficient cDCs was also significantly reduced.Our study identified a new role for p38αin modulating the important antigen cross-presentation function of DCs.
文摘Antigen-presentation via major histocompatibility complex(MHC)to T cells is the key event to initiate adaptive immune responses.In teleosts,as in mammals,the main types of professional antigen-presenting cells(APCs)are dendritic cells(DCs),monocytes/macrophages,and B cells.In the current study,flow cytometry,immunostaining and qPCR have been used to show that neutrophils in the teleost fish Atlantic salmon(Salmo salar L.)have antigen-presenting properties.The neutrophils were positive for MHC class II,CD83 and CD80/86,and upon in vitro bacterial exposure,gene expression analysis of purified neutrophils showed that IL-12p40,which is essential for proliferation of naïve T cells,was highly upregulated at both 6 and 24 h post bacterial exposure.Based on presence of MHC class II and upregulation of molecules involved in antigen presentation and T cell activation,we suggest that neutrophils in Atlantic salmon have potential to function as professional APCs.This work makes an important basis for further exploring the potential of using neutrophils to develop new,targeted immunoprophylactic measures.
基金supported by the National Natural Science Foundation of China(31830022 and 81621001)the Chinese Ministry of Science and Technology(2019YFA0508500).
文摘Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines.To date,only a few adjuvants have been approved for use in humans,among which aluminum-containing adjuvants are the only ones widely used.However,the medical need for potent and safe adjuvants is currently continuously increasing,especially those triggering cellular immune responses for cytotoxic T lymphocyte activation,which are urgently needed for the development of efficient virus and cancer vaccines.Manganese is an essential micronutrient required for diverse biological activities,but its functions in immunity remain undefined.We previously reported that Mn^(2+) is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn^(2+)alone directly activates cGAS independent of dsDNA,leading to an unconventional catalytic synthesis of 2′3′-cGAMP.Herein,we found that Mn^(2+) strongly promoted immune responses by facilitating antigen uptake,presentation,and germinal center formation via both cGAS-STING and NLRP3 activation.Accordingly,a colloidal manganese salt(Mn jelly,MnJ)was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses,inducing antibody production and CD4^(+)/CD8^(+)T-cell proliferation and activation by either intramuscular or intranasal immunization.When administered intranasally,MnJ also worked as a mucosal adjuvant,inducing high levels of secretory IgA.MnJ showed good adjuvant effects for all tested antigens,including T cell-dependent and T cell-independent antigens,such as bacterial capsular polysaccharides,thus indicating that it is a promising adjuvant candidate.
基金supported by grants:National Natural Science Foundation of China (82072087,31670880 and 31970893,China)Guangdong Natural Science Fund for Distinguished Young Scholars (2017A030306016 and 2016A030306004,China)+1 种基金the Fundamental Research Funds for the Central Universities (19ykzd39,China)Open project of Guangdong Key Laboratory of Chiral Molecule and Drug Discovery (Sun Yat-sen University,China)。
文摘Stimulator of interferon genes(STING) is a cytosolic DNA sensor which is regarded as a potential target for antitumor immunotherapy. However, clinical trials of STING agonists display limited anti-tumor effects and dose-dependent side-effects like inflammatory damage and cell toxicity. Here,we showed that tetrahedral DNA nanostructures(TDNs) actively enter macrophages to promote STING activation and M1 polarization in a size-dependent manner, and synergized with Mn^(2+) to enhance the expressions of IFN-β and iNOS, as well as the co-stimulatory molecules for antigen presentation. Moreover, to reduce the cytotoxicity of Mn^(2+),we constructed a TDN-MnO_(2) complex and found that it displayed a much higher efficacy than TDN plus Mn^(2+) to initiate macrophage activation and anti-tumor response both in vitro and in vivo. Together, our studies explored a novel immune activation effect of TDN in cancer therapy and its synergistic therapeutic outcomes with MnO_(2).These findings provide new therapeutic opportunities for cancer therapy.
基金This work was partially supported by the National Key R&D Program of China(No.2017YFA0205600)the National Natural Science Foundation of China(Nos.31870996 and 32071378)+6 种基金Outstanding Scholar Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(No.2018GZR110102001)the Program for Guangdong Introducing Innovative and Entrepreneurial Teams(No.2017ZT07S054)Guangdong Provincial Pearl River Talents Program(No.2017GC010482)Guangdong Basic and Applied Basic Research Foundation(No.2020A1515011297)the Natural Science Foundation of Guangdong Province,China(No.2019A1515011926)the China Postdoctoral Science Foundation(No.2018M643096)the Fundamental Research Funds for the Central Universities.
文摘Tumor immunotherapy as a promising method for tumor treatment received tremendous attention. However, the problem of low clinical response rate still needs to be solved, especially in the poorly immunogenic tumors. The enhancement of tumor antigens presentation can effectively activate dendritic cells (DCs) and improve the tumor immunotherapy. In this work, TAK-243 as an inhibitor of the ubiquitin activating enzyme (UAE), was fabricated into cationic lipid-assisted nanoparticle (CLANTAK-243). The obtained CLANTAK-243 could act as an effective tumor immunotherapy enhancer to promote the maturation of DCs as well as antigen presentation, which obviously stimulated the T cells activation and proliferation. Such CLANTAK-243 injected intravenously could well trigger immune response to tumor cells in vivo. Importantly, mice treated with CLANTAK-243 could obtain a long immune memory effect to protect themselves from re-challenged tumor cells. Therefore, this work presented an effective immunotherapy strategy for poorly immunogenic tumor.
文摘T cell recognition of foreign peptide antigen and toler-ance to self peptides is key to the proper function of the immune system.Usually,in the thymus T cells that rec-ognize self MHC+self peptides are deleted and those with the potential to recognize self MHC+foreign pep-tides are selected to mature.However there are excep-tions to these rules.Autoimmunity and allergy are two of the most common immune diseases that can be related to recognition of self.Many genes work together to lead to autoimmunity.Of those,particular MHC alleles are the most strongly associated,reflecting the key importance of MHC presentation of self peptides in autoimmunity.T cells specific for combinations of self MHC and self pep-tides may escape thymus deletion,and thus be able to drive autoimmunity,for several reasons:the relevant self peptide may be presented at low abundance in the thy-mus but at high level in particular peripheral tissues;the relevant self peptide may bind to MHC in an unusual register,not present in the thymus but apparent else-where;finally the relevant self peptide may be post translationally modified in a tissue specific fashion.In some types of allergy,the peptide+MHC combination may also be fully derived from self.However the combi-nation in question may be modified by the presence of other ligands,such as small drug molecules or metal ions.Thus these types of allergies may act like the post translationally modified peptides involved some types of autoimmunity.
基金OCSC Royal Thai Government-UCAS Scholarship under research collaboration between National Nanotechnology Center(NANOTEC),Thailand,and National Center for Nanoscience and Technology,China(No.P1852764)This work was also supported by the National Natural Science Foundation of China(NSFC)key projects(Nos.31630027 and 32030060)+4 种基金NSFC international collaboration key project(No.51861135103)NSFC-German Research Foundation(DFG)project(No.31761133013)The authors also appreciate the support by“the Beijing-Tianjin-Hebei Basic Research Cooperation Project”(No.19JCZDJC64100)National Key Research&Development Program of China(No.2018YFE0117800)The authors are grateful for Prof.Dr.S.Seraphin at the Professional Authorship Center,Thailand National Science,and Technology Development Agency(NSTDA)for fruitful discussions on the manuscript preparation.
文摘Vaccination is the most effective way to prevent coronavirus disease 2019(COVID-19).Vaccine development approaches consist of viral vector vaccines,DNA vaccine,RNA vaccine,live attenuated virus,and recombinant proteins,which elicit a specific immune response.The use of nanoparticles displaying antigen is one of the alternative approaches to conventional vaccines.This is due to the fact that nano-based vaccines are stable,able to target,form images,and offer an opportunity to enhance the immune responses.The diameters of ultrafine nanoparticles are in the range of 1–100 nm.The application of nanotechnology on vaccine design provides precise fabrication of nanomaterials with desirable properties and ability to eliminate undesirable features.To be successful,nanomaterials must be uptaken into the cell,especially into the target and able to modulate cellular functions at the subcellular levels.The advantages of nano-based vaccines are the ability to protect a cargo such as RNA,DNA,protein,or synthesis substance and have enhanced stability in a broad range of pH,ambient temperatures,and humidity for long-term storage.Moreover,nano-based vaccines can be engineered to overcome biological barriers such as nonspecific distribution in order to elicit functions in antigen presenting cells.In this review,we will summarize on the developing COVID-19 vaccine strategies and how the nanotechnology can enhance antigen presentation and strong immunogenicity using advanced technology in nanocarrier to deliver antigens.The discussion about their safe,effective,and affordable vaccines to immunize against COVID-19 will be highlighted.
