AIM:To investigate possible differences in dendritic cells(DC)within intestinal tissue of mice before and after induction of colitis. METHODS:Mucosal DC derived from intestinal tissue,as well as from mesenteric lymph ...AIM:To investigate possible differences in dendritic cells(DC)within intestinal tissue of mice before and after induction of colitis. METHODS:Mucosal DC derived from intestinal tissue,as well as from mesenteric lymph nodes and spleen,were analyzed by fluorescence activated cell sorting(FACS) analysis.Supernatants of these cells were analyzed for secretion of different pro-and anti-inflammatory cytokines. Immunohistochemistry and immunofluorescence were performed on cryosections of mucosal tissue derived from animals with colitis as well as from healthy mice. RESULTS:It was shown that DC derived from healthy intestinal lamina propria(LP)represented an immature phenotype as characterized by low-level expression of costimulatory cytokines.In contrast to DC from spleen and mesenteric lymph nodes(MLN)that secreted proinflammatory cytokines,LP-DC produced high levels of the anti-inflammatory cytokine IL-10.After induction of mu-rine colitis in a CD4 + CD62L + transfer model or in chronic Dextran sulfate sodium-colitis,a marked increase of activated CD80 + DC could be observed within the inflamed colonic tissue.Interestingly,in contrast to splenic DC,a significant population of DC within MLN and colonic LP expressed the mucosal integrin CD103 which was lost during colitis. CONCLUSION:The constitutive secretion of antiinflammatory cytokines by immature DC within the intestinal LP might regulate the homeostatic balance between mucosal immunity and tolerance.CD103 + DC could mediate this important function.展开更多
Background Immune cell heterogenicity is known to determine the therapeutic response to cancer progression.Neoadjuvant chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck s...Background Immune cell heterogenicity is known to determine the therapeutic response to cancer progression.Neoadjuvant chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma(HNSCC),but the underlying mechanism behind this clinical response is unknown.The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting NACI response in advanced HNSCC.Methods We performed combined single-cell RNA sequencing(scRNA-seq)and multiplex immunofluorescence(mIHC)staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell(TIL)subtype,CD103^(+)CD8^(+)TILs,associated with clinical response,while both in vitro and in vivo assays were carried out to determine its antitumor efficiency.The regulatory mechanism of the CD103^(+)CD8^(+)TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC images.Results We established intratumoral CD103^(+)CD8^(+)TILs density as a determinant of NACI efficacy in cancers.Our scRNA-seq results indicated that the population of CD103^(+)CD8^(+)TILs was dramatically increased in the responders of NACI-treated HNSCC patients,while mIHC analysis confirmed the correlation between intratumoral CD103^(+)CD8^(+)TILs density and NACI efficacy in HNSCC patients.Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI.Functional assays showed that CD103^(+)CD8^(+)TILs were tumor-reactive T cells,while programmed cell death protein-1(PD-1)blockade enhanced CD103^(+)CD8^(+)TILs cytotoxicity against tumor growth in vivo.Mechanistically,targeting the triggering receptor expressed on myeloid cells 2-positive(TREM2^(+))macrophages might enhance the population of CD103^(+)CD8^(+)TILs and facilitate antitumor immunity during NACI treatment.Conclusions Our study highlights the impact of intratumoral CD103^(+)CD8^(+)TILs density on NACI efficacy in different cancers,while the efforts to elevate its population warrant further clinical investigation.展开更多
Acute viral infection causes illness and death.In addition,an infection often results in increased susceptibility to a secondary infection,but the mechanisms behind this susceptibility are poorly understood.Since its ...Acute viral infection causes illness and death.In addition,an infection often results in increased susceptibility to a secondary infection,but the mechanisms behind this susceptibility are poorly understood.Since its initial identification as a marker for resident memory CD8^(+)T cells in barrier tissues,the function and regulation of CD103 integrin(encoded by ITGAE gene)have been extensively investigated.Nonetheless,the function and regulation of the resident CD103^(+)CD8^(+)T cell response to acute viral infection remain unclear.Although TGFβsignaling is essential for CD103 expression,the precise molecular mechanism behind this regulation is elusive.Here,we reveal a TGFβ–SKI–Smad4 pathway that critically and specifically directs resident CD103^(+)CD8^(+)T cell generation for protective immunity against primary and secondary viral infection.We found that resident CD103^(+)CD8^(+)T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice.CD103 acts as a costimulation signal to produce an optimal antigenic CD8^(+)T cell response to acute viral infection.There is a reduction in resident CD103^(+)CD8^(+)T cells following primary infection that results in increased susceptibility of the host to secondary infection.Intriguingly,CD103 expression inversely and specifically correlates with SKI proto-oncogene(SKI)expression but not R-Smad2/3 activation.Ectopic expression of SKI restricts CD103 expression in CD8^(+)T cells in vitro and in vivo to hamper viral clearance.Mechanistically,SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner.Our study therefore reveals that resident CD103^(+)CD8^(+)T cells dictate protective immunity during primary and secondary infection.Interfering with SKI function may amplify the resident CD103^(+)CD8^(+)T cell response to promote protective immunity.展开更多
Since the discovery of dendritic cells(DCs)by the Nobel laureate Professor Ralph Steinman et al.in 1973,a plethora of literature has accumulated on the functional roles of DCs in humans and animal models.1 DCs are inv...Since the discovery of dendritic cells(DCs)by the Nobel laureate Professor Ralph Steinman et al.in 1973,a plethora of literature has accumulated on the functional roles of DCs in humans and animal models.1 DCs are involved in the innate sensing and modulation of adaptive immunity to pathogens.CD103+DCs constitute a classical nonlymphoid DC subset that has an important role in generating immunity and maintaining tolerance.2 Pulmonary CD103+DCs(CD103+PDCs),which reside in close association with the airway epithelium,are particularly critical in controlling Tcell immunity against lung infections.2,3 In this article,we discuss recent evidence that shines light on the role and mechanism of CD103+PDCs in modulating CD8+and CD4+T-cell responses against various pathogens,including bacteria and viruses.A deeper understanding of CD103+PDC function may provide new translational avenues for the development of vaccines and therapeutics against infectious diseases.展开更多
基金supported by the National Natural Science Foundation of China(No. 81470222)the Science and Technology Project of Chongqing(No. cstc2017jcyj B0160)the Science and Technology Project of Yuzhong District,Chongqing(No. 20170120)
基金Supported by Grants From the German Research Foundation DFG[UGS(FOR 876),FO,HCR]Research Grants From the University of Regensburg,Germany as part of the ReForM-program(UGS,FO)
文摘AIM:To investigate possible differences in dendritic cells(DC)within intestinal tissue of mice before and after induction of colitis. METHODS:Mucosal DC derived from intestinal tissue,as well as from mesenteric lymph nodes and spleen,were analyzed by fluorescence activated cell sorting(FACS) analysis.Supernatants of these cells were analyzed for secretion of different pro-and anti-inflammatory cytokines. Immunohistochemistry and immunofluorescence were performed on cryosections of mucosal tissue derived from animals with colitis as well as from healthy mice. RESULTS:It was shown that DC derived from healthy intestinal lamina propria(LP)represented an immature phenotype as characterized by low-level expression of costimulatory cytokines.In contrast to DC from spleen and mesenteric lymph nodes(MLN)that secreted proinflammatory cytokines,LP-DC produced high levels of the anti-inflammatory cytokine IL-10.After induction of mu-rine colitis in a CD4 + CD62L + transfer model or in chronic Dextran sulfate sodium-colitis,a marked increase of activated CD80 + DC could be observed within the inflamed colonic tissue.Interestingly,in contrast to splenic DC,a significant population of DC within MLN and colonic LP expressed the mucosal integrin CD103 which was lost during colitis. CONCLUSION:The constitutive secretion of antiinflammatory cytokines by immature DC within the intestinal LP might regulate the homeostatic balance between mucosal immunity and tolerance.CD103 + DC could mediate this important function.
基金supported by the National Natural Science Foundation of China(82272788,82072990,81903045,and 82072988)China Postdoctoral Science Foundation(2021M703692)+2 种基金Department of Health of Guangdong Province Science Foundation(A2022165 and A2021142)Guangzhou Municipal Science and Technology Project(202201011479)Guangdong Science and Technology Development Fund(2019A1515011867 and 2020A1515010405).
文摘Background Immune cell heterogenicity is known to determine the therapeutic response to cancer progression.Neoadjuvant chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma(HNSCC),but the underlying mechanism behind this clinical response is unknown.The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting NACI response in advanced HNSCC.Methods We performed combined single-cell RNA sequencing(scRNA-seq)and multiplex immunofluorescence(mIHC)staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell(TIL)subtype,CD103^(+)CD8^(+)TILs,associated with clinical response,while both in vitro and in vivo assays were carried out to determine its antitumor efficiency.The regulatory mechanism of the CD103^(+)CD8^(+)TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC images.Results We established intratumoral CD103^(+)CD8^(+)TILs density as a determinant of NACI efficacy in cancers.Our scRNA-seq results indicated that the population of CD103^(+)CD8^(+)TILs was dramatically increased in the responders of NACI-treated HNSCC patients,while mIHC analysis confirmed the correlation between intratumoral CD103^(+)CD8^(+)TILs density and NACI efficacy in HNSCC patients.Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI.Functional assays showed that CD103^(+)CD8^(+)TILs were tumor-reactive T cells,while programmed cell death protein-1(PD-1)blockade enhanced CD103^(+)CD8^(+)TILs cytotoxicity against tumor growth in vivo.Mechanistically,targeting the triggering receptor expressed on myeloid cells 2-positive(TREM2^(+))macrophages might enhance the population of CD103^(+)CD8^(+)TILs and facilitate antitumor immunity during NACI treatment.Conclusions Our study highlights the impact of intratumoral CD103^(+)CD8^(+)TILs density on NACI efficacy in different cancers,while the efforts to elevate its population warrant further clinical investigation.
基金This work was supported by NIH funding(R01Al143894,R01Al138337)for J.K.W.the NIH(Al123193)+1 种基金the National Multiple Sclerosis Society(RG-1802-30483)the Yang Family Biomedical Scholars Award for Y.Y.W.
文摘Acute viral infection causes illness and death.In addition,an infection often results in increased susceptibility to a secondary infection,but the mechanisms behind this susceptibility are poorly understood.Since its initial identification as a marker for resident memory CD8^(+)T cells in barrier tissues,the function and regulation of CD103 integrin(encoded by ITGAE gene)have been extensively investigated.Nonetheless,the function and regulation of the resident CD103^(+)CD8^(+)T cell response to acute viral infection remain unclear.Although TGFβsignaling is essential for CD103 expression,the precise molecular mechanism behind this regulation is elusive.Here,we reveal a TGFβ–SKI–Smad4 pathway that critically and specifically directs resident CD103^(+)CD8^(+)T cell generation for protective immunity against primary and secondary viral infection.We found that resident CD103^(+)CD8^(+)T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice.CD103 acts as a costimulation signal to produce an optimal antigenic CD8^(+)T cell response to acute viral infection.There is a reduction in resident CD103^(+)CD8^(+)T cells following primary infection that results in increased susceptibility of the host to secondary infection.Intriguingly,CD103 expression inversely and specifically correlates with SKI proto-oncogene(SKI)expression but not R-Smad2/3 activation.Ectopic expression of SKI restricts CD103 expression in CD8^(+)T cells in vitro and in vivo to hamper viral clearance.Mechanistically,SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner.Our study therefore reveals that resident CD103^(+)CD8^(+)T cells dictate protective immunity during primary and secondary infection.Interfering with SKI function may amplify the resident CD103^(+)CD8^(+)T cell response to promote protective immunity.
文摘Since the discovery of dendritic cells(DCs)by the Nobel laureate Professor Ralph Steinman et al.in 1973,a plethora of literature has accumulated on the functional roles of DCs in humans and animal models.1 DCs are involved in the innate sensing and modulation of adaptive immunity to pathogens.CD103+DCs constitute a classical nonlymphoid DC subset that has an important role in generating immunity and maintaining tolerance.2 Pulmonary CD103+DCs(CD103+PDCs),which reside in close association with the airway epithelium,are particularly critical in controlling Tcell immunity against lung infections.2,3 In this article,we discuss recent evidence that shines light on the role and mechanism of CD103+PDCs in modulating CD8+and CD4+T-cell responses against various pathogens,including bacteria and viruses.A deeper understanding of CD103+PDC function may provide new translational avenues for the development of vaccines and therapeutics against infectious diseases.
