Liver sinusoidal endothelial cells （LSECs） line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident ...Liver sinusoidal endothelial cells （LSECs） line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident immune cell populations such as Kupffer cells, innate lymphoid cells or liver dendritic cells. In addition to having an extraordinary scavenger function, LSECs possess potent immune functions, serving as sentinel cells to detect microbial infection through pattern recognition receptor activation and as antigen （cross）-presenting cells. LSECs cross-prime naive CD8 T cells, causing their rapid differentiation into memory T cells that relocate to secondary lymphoid tissues and provide protection when they re-encounter the antigen during microbial infection. Cross-presentation of viral antigens by LSECs derived from infected hepatocytes triggers local activation of effector CD8 T cells and thereby assures hepatic immune surveillance. The immune function of LSECs complements conventional immune-activating mechanisms to accommodate optimal immune surveillance against infectious microorganisms while preserving the integrity of the liver as a metabolic organ.展开更多
The clinical success of immune checkpoint therapy(ICT)has produced explosive growth in tumor immunology research because ICT was discovered through basic studies of immune regulation.Much of the current translational ...The clinical success of immune checkpoint therapy(ICT)has produced explosive growth in tumor immunology research because ICT was discovered through basic studies of immune regulation.Much of the current translational efforts are aimed at enhancing ICT by identifying therapeutic targets that synergize with CTLA4 or PD1/PD-L1 blockade and are solidly developed on the basis of currently accepted principles.Expanding these principles through continuous basic research may help broaden translational efforts.With this mindset,we focused this review on three threads of basic research directly relating to mechanisms underlying ICT.Specifically,this review covers three aspects of dendritic cell(DC)biology connected with antitumor immune responses but are not specifically oriented toward therapeutic use.First,we review recent advances in the development of the cDC1 subset of DCs,identifying important features distinguishing these cells from other types of DCs.Second,we review the antigen-processing pathway called cross-presentation,which was discovered in the mid-1970s and remains an enigma.This pathway serves an essential in vivo function unique to cDC1s and may be both a physiologic bottleneck and therapeutic target.Finally,we review the longstanding field of helper cells and the related area of DC licensing,in which CD4 T cells influence the strength or quality of CD8 T cell responses.Each topic is connected with ICT in some manner but is also a fundamental aspect of cell-mediated immunity directed toward intracellular pathogens.展开更多
Cancer vaccines aimed at expanding the pool or increasing the activity of tumor-specific T cells against malignancies is an important immunotherapy modality that has been extensively pursued in the past decades. Howev...Cancer vaccines aimed at expanding the pool or increasing the activity of tumor-specific T cells against malignancies is an important immunotherapy modality that has been extensively pursued in the past decades. However, the clinical efficacy of cancer vaccines remains modest in comparison to other immunotherapies, such as checkpoint blockade and adoptive T cell therapy. This unsatisfactory performance is likely due to the suboptimal selection of tumor antigens for vaccine and inefficient delivery platform. Recently, vaccines designed to target cancer neoantigens have shown marked promise in both preclinical and early clinical studies. However, enormous challenges need to be overcome to develop a highly efficient and safe delivery strategy for targeting cancer vaccines to professional antigen-presenting cells and eliciting optimized immune response against cancers. To meet these challenges, biomaterials, particularly biomaterials that are designed to respond to certain environmental stimuli, termed as stimuli-responsive biomaterials, are being actively developed to precisely manipulate the trafficking and release of cancer vaccines in vivo for enhanced therapeutic efficacy and safety. In this mini review, we provide a brief overview of the recent advances in applying stimuli-responsive biomaterials in enhancing non-cellular cancer vaccines while focusing on the chemistry and material design with varied responsiveness. We also discuss the present challenges and opportunities in the field and provide a perspective for future directions.展开更多
Cancer vaccines represent a promising immunotherapeutic treatment modality.The promotion of cross-presentation of extracellular tumor-associated antigens on the major histocompatibility complex(MHC) class I molecules ...Cancer vaccines represent a promising immunotherapeutic treatment modality.The promotion of cross-presentation of extracellular tumor-associated antigens on the major histocompatibility complex(MHC) class I molecules and dendritic cell maturation at the appropriate time and place is crucial for cancer vaccines to prime cytolytic T cell response with reduced side effects.Current vaccination strategies,however,are not able to achieve the spatiotemporal control of antigen cross-presentation.Here,we report a liposomal vaccine loading the second near-infrared window(NIR-II,1000—1700 nm) fluorophore BPBBT with an efficient photothermal conversion effect that offers an NIR-light-triggered endolysosomal escape under the imaging guidance.The NIR-II image-guided vaccination strategy specifically controls the cytosolic delivery of antigens for cross-presentation in the draining lymph nodes(DLNs).Moreover,the photothermally induced endolysosomal rupture initiates autophagy.We also find that the adjuvant simvastatin acts as an autophagy activator through inhibiting the PI3K/AKT/m TOR pathway.The light-induced autophagy in the DLNs together with simvastatin treatment cooperatively increase MHC class II expression by activating autophagy machinery for dendritic cell maturation.This study presents a paradigm of NIR-II image-guided light-triggered vaccination.The approach for remote control of antigen cross-presentation and autophagy represents a new strategy for vaccine development.展开更多
The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictab...The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictable metabolism,and potential systemic toxicity,which bring obstacles for their clinical translation.Herein,we developed an antigen self-assembled nanovaccine,which was resulted from a simple acryloyl modification of the antigen to induce self-assembly.Furthermore,a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid(Zol)were integrated or absorbed onto the nanoparticles(denoted as MEAO-Z)to intensify the immune response.The synthesized nano vaccine with a diameter of around 70 nm showed successful lymph node transportation,high dendritic cell internalization,promoted costimulatory molecule expression,and preferable antigen cross-presentation.In virtue of the above superiorities,MEAO-Z induced remarkably higher titers of serum antibody,stronger cytotoxic T lymphocyte immune responses and IFN-γsecretion than free antigen and adjuvants.In vivo,MEAO-Z significantly suppressed EG7-OVA tumor groth and prolonged the survival time of tumor-bearing mice.These results indicated the translation promise of our self-assembled nano vaccine for immune potentiation and cancer immunotherapy.展开更多
Certain chemo drugs have been reported to potentially induce tumor-specific immune recognition by triggering immunogenic cell death(ICD),which provides a promising alternative way for cancer immunotherapy.However,the ...Certain chemo drugs have been reported to potentially induce tumor-specific immune recognition by triggering immunogenic cell death(ICD),which provides a promising alternative way for cancer immunotherapy.However,the immunogenic effects of such treatments are still weak and robust systemic antitumor immune responses are rarely seen when these agents were used alone.Herein,we proposed a trinity immune enhancing nanoparticles(TIENs)for boosting antitumor immune responses of chemo agents.The TIENs was constructed with Food and Drug Administration(FDA)approved polylactic acid(PLA),canonical proton-sponging cationic polymer polyethyleneimine(PEI),and Toll-like receptor 9(TLR9)agonist cytosine phosphate guanine oligodeoxynucleotide(CpG-ODN).In in vitro studies,the TIENs was proved to(1)promote antigen capturing,(2)antigen-presenting cells(APCs)activation,and(3)antigen cross-presentation.In in vivo studies,intratumorally injected TIENs greatly enhanced antitumor effect and robust immune responses of oxaliplatin and doxorubicin in murine CT26 and 4T1 tumor models,respectively.Furthermore,after decoration with a detachable shielding,the TIENs was proved to be effective in promoting the antitumor effects of chemo agents after intravenous injection.The combination of TIENs with clinically widely used chemo agents should be meaningful in boosting effective antitumor immune responses and cancer therapy.展开更多
Cancer vaccine contributing to the success of the treatment and prevention of tumors has attracted a huge attention as a strategy for tumor immunotherapy in recent years.A major challenge of cancer vaccine is to targe...Cancer vaccine contributing to the success of the treatment and prevention of tumors has attracted a huge attention as a strategy for tumor immunotherapy in recent years.A major challenge of cancer vaccine is to target cytosols of dendritic cells(DCs)in the lymph nodes(LNs)to enhance efficiency of antigen cross-presentation,which elicits high levels of cytotoxic T-lymphocytes to destruct tumor cells.Here,we address this issue by conjugating ovalbumin(OVA)to PEG-PCL using disulfide bond(-ss-),and the degradable pH-responsive polymer-PEI-PCL as delivery carrier.In addition,the mol ratio of PEG-PCL to PEI-PCL in the mixed micelles was tailored to deliver the OVA to LNs.Subsequently,CpG ODN_(1826),a TLR-9 agonist,was further introduced into a mixed micelle of 30nm or less as a unique tumor vaccine.Importantly,the results demonstrated the mixed micelles with 1:1mol of PCL-PEG and PCL-PEI can effectively migrate to distal LNs where antigen were efficiently captured by DCs,meanwhile,OVA was modified to the surface of mixed micelles via disulfide bonds(-ss-)for promotion efficiency of antigen cross-presentation.More surprisingly,combination of tumor vaccine with anti-PD-1,the therapy of ectopic melanoma(B16-OVA)and lung metastasis melanoma(B16-OVA)is excellent therapeutic effect.Taken together,our works offers a novel strategy for the cytosol delivery of antigens to achieve potent cancer immunotherapy.展开更多
Interleukin-15(IL-15)is a pro-inflammatory cytokine that is required for the survival and activation of memory CD8^(+)T cells,natural killer(NK)cells,innate lymphoid cells,macrophages and dendritic cells.IL-15 is impl...Interleukin-15(IL-15)is a pro-inflammatory cytokine that is required for the survival and activation of memory CD8^(+)T cells,natural killer(NK)cells,innate lymphoid cells,macrophages and dendritic cells.IL-15 is implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis,inflammatory bowel disease,psoriasis and autoimmune type 1 diabetes(T1D).IL-15 receptor(IL-15R)consists of a specificαchain,theβchain that is shared with IL-2R and the commonγchain.IL-15 is unique in the manner in which it binds and signals through its receptor subunits.IL-15 that is complexed with IL-15Rαbinds to theβγreceptor complex present on the responding cell to mediate its biological effects through a process referred to as trans-presentation.The trans-presented IL-15 is essential to mediate the biological effects on T lymphocytes and NK cells.Here we show that IL-15,but not IL-15Rα,is required for the development of spontaneous and virus-induced T1D,viral clearance and for antigen cross-presentation to CD8^(+)T lymphocytes.Our findings provide insight into the complexities of IL-15 signalling in the initiation and maintenance of CD8^(+)T cell-mediated immune responses.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
The potential of the skin immune system to generate immune responses is well established, and the skin is actively exploited as a vaccination site. Human skin contains several antigen-presenting cell subsets with spec...The potential of the skin immune system to generate immune responses is well established, and the skin is actively exploited as a vaccination site. Human skin contains several antigen-presenting cell subsets with specialized functions. In particular, the capacity to cross-present exogenous antigens to CD8^＋ T cells is of interest for the design of effective immunotherapies against viruses or cancer. Here, we show that primary human Langerhans cells （LCs） were able to cross-present a synthetic long peptide （SLP） to CD8^＋ T cells. In addition, modification of this SLP using antibodies against the receptor langerin, but not dectin-1, further enhanced the cross-presenting capacity of LCs through routing of internalized antigens to less proteolytic early endosome antigen 1 ^＋ early endosomes. The potency of LCs to enhance CD8^＋ T-cell responses could be further increased through activation of LCs with the toll-like receptor 3 ligand polyinosinic：polycytidylic acid （phC）. Altogether, the data provide evidence that human LCs are able to cross-present antigens after langerin-mediated internalization. Furthermore, the potential for antigen modification to target LCs specifically provides a rationale for generating effective anti-tumor or anti-viral cytotoxic T lymphocyte responses.展开更多
文摘Liver sinusoidal endothelial cells （LSECs） line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident immune cell populations such as Kupffer cells, innate lymphoid cells or liver dendritic cells. In addition to having an extraordinary scavenger function, LSECs possess potent immune functions, serving as sentinel cells to detect microbial infection through pattern recognition receptor activation and as antigen （cross）-presenting cells. LSECs cross-prime naive CD8 T cells, causing their rapid differentiation into memory T cells that relocate to secondary lymphoid tissues and provide protection when they re-encounter the antigen during microbial infection. Cross-presentation of viral antigens by LSECs derived from infected hepatocytes triggers local activation of effector CD8 T cells and thereby assures hepatic immune surveillance. The immune function of LSECs complements conventional immune-activating mechanisms to accommodate optimal immune surveillance against infectious microorganisms while preserving the integrity of the liver as a metabolic organ.
文摘The clinical success of immune checkpoint therapy(ICT)has produced explosive growth in tumor immunology research because ICT was discovered through basic studies of immune regulation.Much of the current translational efforts are aimed at enhancing ICT by identifying therapeutic targets that synergize with CTLA4 or PD1/PD-L1 blockade and are solidly developed on the basis of currently accepted principles.Expanding these principles through continuous basic research may help broaden translational efforts.With this mindset,we focused this review on three threads of basic research directly relating to mechanisms underlying ICT.Specifically,this review covers three aspects of dendritic cell(DC)biology connected with antitumor immune responses but are not specifically oriented toward therapeutic use.First,we review recent advances in the development of the cDC1 subset of DCs,identifying important features distinguishing these cells from other types of DCs.Second,we review the antigen-processing pathway called cross-presentation,which was discovered in the mid-1970s and remains an enigma.This pathway serves an essential in vivo function unique to cDC1s and may be both a physiologic bottleneck and therapeutic target.Finally,we review the longstanding field of helper cells and the related area of DC licensing,in which CD4 T cells influence the strength or quality of CD8 T cell responses.Each topic is connected with ICT in some manner but is also a fundamental aspect of cell-mediated immunity directed toward intracellular pathogens.
基金This work was supported in part by the Foundation Pierre Mercier pour la science, ISREC Foundation with a donation from the Bateman Foundation, Swiss National Science Foundation （Project grant 315230 173243）, Novartis Foundation for medical-biological Research （17A058）, and the Ecole polytechnique federale de Lausanne （EPFL）.
文摘Cancer vaccines aimed at expanding the pool or increasing the activity of tumor-specific T cells against malignancies is an important immunotherapy modality that has been extensively pursued in the past decades. However, the clinical efficacy of cancer vaccines remains modest in comparison to other immunotherapies, such as checkpoint blockade and adoptive T cell therapy. This unsatisfactory performance is likely due to the suboptimal selection of tumor antigens for vaccine and inefficient delivery platform. Recently, vaccines designed to target cancer neoantigens have shown marked promise in both preclinical and early clinical studies. However, enormous challenges need to be overcome to develop a highly efficient and safe delivery strategy for targeting cancer vaccines to professional antigen-presenting cells and eliciting optimized immune response against cancers. To meet these challenges, biomaterials, particularly biomaterials that are designed to respond to certain environmental stimuli, termed as stimuli-responsive biomaterials, are being actively developed to precisely manipulate the trafficking and release of cancer vaccines in vivo for enhanced therapeutic efficacy and safety. In this mini review, we provide a brief overview of the recent advances in applying stimuli-responsive biomaterials in enhancing non-cellular cancer vaccines while focusing on the chemistry and material design with varied responsiveness. We also discuss the present challenges and opportunities in the field and provide a perspective for future directions.
基金supported in part by grants from National Natural Science Foundation of China(No.81991493,China)Shanghai Municipal Health Commission(No.2022XD045,China)。
文摘Cancer vaccines represent a promising immunotherapeutic treatment modality.The promotion of cross-presentation of extracellular tumor-associated antigens on the major histocompatibility complex(MHC) class I molecules and dendritic cell maturation at the appropriate time and place is crucial for cancer vaccines to prime cytolytic T cell response with reduced side effects.Current vaccination strategies,however,are not able to achieve the spatiotemporal control of antigen cross-presentation.Here,we report a liposomal vaccine loading the second near-infrared window(NIR-II,1000—1700 nm) fluorophore BPBBT with an efficient photothermal conversion effect that offers an NIR-light-triggered endolysosomal escape under the imaging guidance.The NIR-II image-guided vaccination strategy specifically controls the cytosolic delivery of antigens for cross-presentation in the draining lymph nodes(DLNs).Moreover,the photothermally induced endolysosomal rupture initiates autophagy.We also find that the adjuvant simvastatin acts as an autophagy activator through inhibiting the PI3K/AKT/m TOR pathway.The light-induced autophagy in the DLNs together with simvastatin treatment cooperatively increase MHC class II expression by activating autophagy machinery for dendritic cell maturation.This study presents a paradigm of NIR-II image-guided light-triggered vaccination.The approach for remote control of antigen cross-presentation and autophagy represents a new strategy for vaccine development.
基金financially supported by the National Natural Science Foundation of China(81925036&81872814)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2020YFS0570,China)+2 种基金Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System(CARS-SVDIP)111 project(b18035,China)the Fundamental Research Funds for the Central Universities(China)。
文摘The rise of nanotechnology has opened new horizons for cancer immunotherapy.However,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictable metabolism,and potential systemic toxicity,which bring obstacles for their clinical translation.Herein,we developed an antigen self-assembled nanovaccine,which was resulted from a simple acryloyl modification of the antigen to induce self-assembly.Furthermore,a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid(Zol)were integrated or absorbed onto the nanoparticles(denoted as MEAO-Z)to intensify the immune response.The synthesized nano vaccine with a diameter of around 70 nm showed successful lymph node transportation,high dendritic cell internalization,promoted costimulatory molecule expression,and preferable antigen cross-presentation.In virtue of the above superiorities,MEAO-Z induced remarkably higher titers of serum antibody,stronger cytotoxic T lymphocyte immune responses and IFN-γsecretion than free antigen and adjuvants.In vivo,MEAO-Z significantly suppressed EG7-OVA tumor groth and prolonged the survival time of tumor-bearing mice.These results indicated the translation promise of our self-assembled nano vaccine for immune potentiation and cancer immunotherapy.
基金supported by the National Natural Science Foundation of China(Nos.51973215,52025035,52003268,51829302,and 51833010)Bureau of International Cooperation Chinese Academy of Sciences(No.121522KYSB20200029)+1 种基金the Jilin Province Science and Technology Development Plan(No.2020122331JC)support from the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2020232).
文摘Certain chemo drugs have been reported to potentially induce tumor-specific immune recognition by triggering immunogenic cell death(ICD),which provides a promising alternative way for cancer immunotherapy.However,the immunogenic effects of such treatments are still weak and robust systemic antitumor immune responses are rarely seen when these agents were used alone.Herein,we proposed a trinity immune enhancing nanoparticles(TIENs)for boosting antitumor immune responses of chemo agents.The TIENs was constructed with Food and Drug Administration(FDA)approved polylactic acid(PLA),canonical proton-sponging cationic polymer polyethyleneimine(PEI),and Toll-like receptor 9(TLR9)agonist cytosine phosphate guanine oligodeoxynucleotide(CpG-ODN).In in vitro studies,the TIENs was proved to(1)promote antigen capturing,(2)antigen-presenting cells(APCs)activation,and(3)antigen cross-presentation.In in vivo studies,intratumorally injected TIENs greatly enhanced antitumor effect and robust immune responses of oxaliplatin and doxorubicin in murine CT26 and 4T1 tumor models,respectively.Furthermore,after decoration with a detachable shielding,the TIENs was proved to be effective in promoting the antitumor effects of chemo agents after intravenous injection.The combination of TIENs with clinically widely used chemo agents should be meaningful in boosting effective antitumor immune responses and cancer therapy.
文摘Cancer vaccine contributing to the success of the treatment and prevention of tumors has attracted a huge attention as a strategy for tumor immunotherapy in recent years.A major challenge of cancer vaccine is to target cytosols of dendritic cells(DCs)in the lymph nodes(LNs)to enhance efficiency of antigen cross-presentation,which elicits high levels of cytotoxic T-lymphocytes to destruct tumor cells.Here,we address this issue by conjugating ovalbumin(OVA)to PEG-PCL using disulfide bond(-ss-),and the degradable pH-responsive polymer-PEI-PCL as delivery carrier.In addition,the mol ratio of PEG-PCL to PEI-PCL in the mixed micelles was tailored to deliver the OVA to LNs.Subsequently,CpG ODN_(1826),a TLR-9 agonist,was further introduced into a mixed micelle of 30nm or less as a unique tumor vaccine.Importantly,the results demonstrated the mixed micelles with 1:1mol of PCL-PEG and PCL-PEI can effectively migrate to distal LNs where antigen were efficiently captured by DCs,meanwhile,OVA was modified to the surface of mixed micelles via disulfide bonds(-ss-)for promotion efficiency of antigen cross-presentation.More surprisingly,combination of tumor vaccine with anti-PD-1,the therapy of ectopic melanoma(B16-OVA)and lung metastasis melanoma(B16-OVA)is excellent therapeutic effect.Taken together,our works offers a novel strategy for the cytosol delivery of antigens to achieve potent cancer immunotherapy.
基金funded by NSERC discovery grant to S.R.S.I.D.B.is a recipient of post-doctoral fellowship from FRQS.
文摘Interleukin-15(IL-15)is a pro-inflammatory cytokine that is required for the survival and activation of memory CD8^(+)T cells,natural killer(NK)cells,innate lymphoid cells,macrophages and dendritic cells.IL-15 is implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis,inflammatory bowel disease,psoriasis and autoimmune type 1 diabetes(T1D).IL-15 receptor(IL-15R)consists of a specificαchain,theβchain that is shared with IL-2R and the commonγchain.IL-15 is unique in the manner in which it binds and signals through its receptor subunits.IL-15 that is complexed with IL-15Rαbinds to theβγreceptor complex present on the responding cell to mediate its biological effects through a process referred to as trans-presentation.The trans-presented IL-15 is essential to mediate the biological effects on T lymphocytes and NK cells.Here we show that IL-15,but not IL-15Rα,is required for the development of spontaneous and virus-induced T1D,viral clearance and for antigen cross-presentation to CD8^(+)T lymphocytes.Our findings provide insight into the complexities of IL-15 signalling in the initiation and maintenance of CD8^(+)T cell-mediated immune responses.
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.
基金We would like to thank the personnel of the Bergman clinic in Bilthoven, the Netherlands for providing healthy donor skin. We would like to thank Tom O＇Toole for the technical assistance with imaging flow cytometry. The present work was funded by KWF （VU2009-2598）, the Dutch Science Foundation （NWO, VENI Grant NO 863.10.017）, the European Research Council （ERCAdvanced339977）, and NanoNext 3D01.
文摘The potential of the skin immune system to generate immune responses is well established, and the skin is actively exploited as a vaccination site. Human skin contains several antigen-presenting cell subsets with specialized functions. In particular, the capacity to cross-present exogenous antigens to CD8^＋ T cells is of interest for the design of effective immunotherapies against viruses or cancer. Here, we show that primary human Langerhans cells （LCs） were able to cross-present a synthetic long peptide （SLP） to CD8^＋ T cells. In addition, modification of this SLP using antibodies against the receptor langerin, but not dectin-1, further enhanced the cross-presenting capacity of LCs through routing of internalized antigens to less proteolytic early endosome antigen 1 ^＋ early endosomes. The potency of LCs to enhance CD8^＋ T-cell responses could be further increased through activation of LCs with the toll-like receptor 3 ligand polyinosinic：polycytidylic acid （phC）. Altogether, the data provide evidence that human LCs are able to cross-present antigens after langerin-mediated internalization. Furthermore, the potential for antigen modification to target LCs specifically provides a rationale for generating effective anti-tumor or anti-viral cytotoxic T lymphocyte responses.
