Gastrointestinal infections are a major cause for serious clinical complications in infants.The induction of antibody responses by B cells is critical for protective immunity against infections and requires CXCR5+PD-1...Gastrointestinal infections are a major cause for serious clinical complications in infants.The induction of antibody responses by B cells is critical for protective immunity against infections and requires CXCR5+PD-1++CD4+T cells(TFH cells).We investigated the ontogeny of CXCR5+PD-1++CD4+T cells in human intestines.While CXCR5+PD-1++CD4+T cells were absent in fetal intestines,CXCR5+PD-1++CD4+T cells increased after birth and were abundant in infant intestines,resulting in significant higher numbers compared to adults.These findings were supported by scRNAseq analyses,showing increased frequencies of CD4+T cells with a TFH gene signature in infant intestines compared to blood.Co-cultures of autologous infant intestinal CXCR5+PD-1+/−CD4+T cells with B cells further demonstrated that infant intestinal TFH cells were able to effectively promote class switching and antibody production by B cells.Taken together,we demonstrate that functional TFH cells are numerous in infant intestines,making them a promising target for oral pediatric vaccine strategies.展开更多
Chronic antigenic stimulation can trigger the differentiation of antigen-experienced CD4+T cells into T regulatory type 1(TR1)cells,a subset of interleukin-10-producing Treg cells that do not express FOxP3.The identit...Chronic antigenic stimulation can trigger the differentiation of antigen-experienced CD4+T cells into T regulatory type 1(TR1)cells,a subset of interleukin-10-producing Treg cells that do not express FOxP3.The identities of the progenitor(s)and transcriptional regulators of this T-cell subset remain unclear.Here,we show that the peptide-major histocompatibility complex class Il(pMHCll)monospecific immunoregulatory T-cell pools that arise in vivo in different genetic backgrounds in response to pMHCll-coated nanoparticles(pMHCll-NPs)are invariably comprised of oligoclonal subpools of T follicular helper(TFH)and TR1 cells with a nearly identical clonotypic composition but different functional properties and transcription factor expression profles.Pseudotime analyses of scRNAseq data and multidimensional mass cytometry revealed progressive downregulation and upregulation of TFH and TR1 markers,respectively.Furthermore,pMHCIl-NPs trigger cognate TR1 cell formation in TFH cell-transfused immunodeficient hosts,and T-cell-specific deletion of Bcl6 or Irf4 blunts both the TFH expansion and TR1 formation induced by pMHCl-NPs.In contrast,deletion of Prdm1 selectively abrogates the TFH-to-TR1 conversion.Bcl6 and Prdm1 are also necessary for anti-CD3 mAbinduced TR1 formation.Thus,TFH cells can differentiate into TR1 cells in vivo,and BLIMP1 is a gatekeeper of this cellular reprogramming event.展开更多
Follicular helper T (TFH) cells represent a distinct subset of CD4+ helper T (TH) cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile (Bcl6), surface m...Follicular helper T (TFH) cells represent a distinct subset of CD4+ helper T (TH) cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile (Bcl6), surface marker expression (CXCR5, PD-1, ICOS and CD4OL) and cytokine production pattern (IL-21 and IL-6). TFH cells provide help to B cells both to form germinal centers (GCs) and to differentiate into memory B cells and plasma cells for generation of humoral responses. However, there is emerging evidence that implicates TFH cells in the development of various human pathologies, such as autoimmune diseases, immunodeficiency and lymphoma. This review focuses on the current progress in this area including mouse and human studies. A clearer understanding of the mechanisms of TFH cell-mediated immunity and pathology may be exploited for rational development of therapeutic strategies. Cellular& Molecular Immunology(2012) 9, 380-385; doi:10.1038/cmi.2012.26; published online 13 August 2012展开更多
A fundamental function of T helper(Th)cells is to regulate B-cell proliferation and immunoglobulin class switching,especially in the germinal centers.Th1 and Th2 lineages of CD41 T cells have long been considered to p...A fundamental function of T helper(Th)cells is to regulate B-cell proliferation and immunoglobulin class switching,especially in the germinal centers.Th1 and Th2 lineages of CD41 T cells have long been considered to play an essential role in helping B cells by promoting the production immunoglobulin G2a(IgG2a)and IgG1/IgE,respectively.Recently,it has become clear that a subset CD41 T cells,named T follicular helper(Tfh)cells,is critical to B-cell response induction.In this review,we summarize the latest advances in our understanding of the regulation of Tfh cell differentiation,the relationship of Tfh cells to other CD41 T-cell lineages,and the role of Tfh cells in health and disease.展开更多
Background:Excessive drinkers(ED)and patients with alcoholic liver disease(ALD)are several times more susceptible to bacterial and viral infections and have a decrease in antibody responses to vaccinations.Follicular ...Background:Excessive drinkers(ED)and patients with alcoholic liver disease(ALD)are several times more susceptible to bacterial and viral infections and have a decrease in antibody responses to vaccinations.Follicular helper T(TFH)cells are essential to select B cells in the germinal center and to produce antibodies.TFH cells express both a membrane-associated and a soluble form of CD40 ligand(sCD40L),in which the latter form is released to circulation upon T cell activation.The effect of alcohol on TFH cells has not been studied.Objectives:The goals of this study are to determine the levels of TFH and T helper 1(Th1)cells in ED and those with alcoholic cirrhosis(AC)when compared to healthy controls and to determine the prognostic significance of sCD40L in a cohort of patients with AC.Methods:Controls,ED,and those with AC were enrolled.Baseline demographic,laboratory tests,and peripheral blood mononuclear cells(PBMCs)were isolated and assessed via flow cytometry for TFH cells.In vitro study was performed to determine the ability of PBMCs to secrete interferon(IFN)-ɣupon stimulation.Serum sCD40L was also determined and its prognostic significance was tested in a cohort of AC patients.Results:The levels of circulating TFH(cTFH)cells were significantly lower in peripheral blood of subjects with ED and AC compared to controls(P<0.05).IFN-ɣsecretion from PBMCs upon stimulation was also lower in ED and those with cirrhosis.Serum sCD40L was significantly lower in ED and AC when compared to that in controls(P<0.0005).Its level was an independent predictor of mortality.Conclusions:Patients with AC had significantly lower level of cTFH and sCD40L.The level of sCD40L was an independent predictor of mortality in these patients.展开更多
Graft versus host disease(GVHD)is a refractory complication of allogeneic hematopoietic stem cell transplantation for the treatment of malignant and non-malignant hematopoietic diseases.Inflammatory cascade responses ...Graft versus host disease(GVHD)is a refractory complication of allogeneic hematopoietic stem cell transplantation for the treatment of malignant and non-malignant hematopoietic diseases.Inflammatory cascade responses and cellular immune reactions are the major factors underlying GVHD pathogenesis.Cells producing the cytokine,interleukin(IL)-21 are crucial players involved in injured tissues in GVHD patients.Besides T helper 17 cells,follicular T helper(Tfh)cells are a new source of IL-21 and play a vital role in GVHD pathogenesis.Tfh cell function is mostly regulated by T-follicular regulatory(Tfr)cells that are also located in the germinal center.This review highlights recent advances in the role of Tfh and Tfr cell function in GVHD pathogenesis.New insights are provided into the potential for clinical application in GVHD prevention and treatment.展开更多
Rabies is a zoonotic disease that still causes 59,000 human deaths each year,and rabies vaccine is the most effective way to control the disease.Our previous studies suggested that the maturation of DC plays an import...Rabies is a zoonotic disease that still causes 59,000 human deaths each year,and rabies vaccine is the most effective way to control the disease.Our previous studies suggested that the maturation of DC plays an important role in enhancing the immunogenicity of rabies vaccine.Flt3L has been reported to own the ability to accelerate the DC maturation,therefore,in this study,a recombinant rabies virus expressing mouse Flt3L,designated as LBNSE-Flt3L,was constructed,and its immunogenicity was characterized.It was found that LBNSE-FU3L could enhance the maturation of DC both in vitro and in vivo,and significantly more TFH cells and Germinal Center B(GC B)cells were generated in mice immunized with LBNSE-FU3L than those immunized with the parent virus LBNSE.Consequently,expressing of Flt3L could elevate the level of virus-neutralizing antibodies(VNA)in immunized mice which provides a better protection from a lethal rabies virus challenge.Taken together,our study extends the potential of Flt3L as a good adjuvant to develop novel rabies vaccine by enhancing the VNA production through activating the DC—Tfh^GC B axis in immunized mice.展开更多
B cell-mediated humoral immunity plays a vital role in viral infections,including chronic hepatitis B virus(HBV)infection,which remains a critical global public health issue.Despite hepatitis B surface antigen-specifi...B cell-mediated humoral immunity plays a vital role in viral infections,including chronic hepatitis B virus(HBV)infection,which remains a critical global public health issue.Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections,the reduced immune functional capacity of B cells was identified,which was also correlated with chronic hepatitis B(CHB)progression.In addition to B cells,T follicular helper(Tfh)cells,which assist B cells to produce antibodies,might also be involved in the process of anti-HBVspecific antibody production.Here,we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity.Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.展开更多
T follicular helper(Tfh)cells are critical in providing help for B cells in the germinal center reaction.Tfh cell plasticity,especially with regard to their expression of effector Th cytokines,has been described,but l...T follicular helper(Tfh)cells are critical in providing help for B cells in the germinal center reaction.Tfh cell plasticity,especially with regard to their expression of effector Th cytokines,has been described,but lacks in-depth analysis with genetic approaches.In this study,we systemically compared transcriptomic profiles of Tfh cells derived from various types of immune responses and found gene clusters corresponding to effector Th cells were differentially induced in response to pathogens or immune responses.Of special interest,a subset of Tfh cells producing IFN-γwas generated in an influenza virus infection,partially dependent on the innate cytokine IL-12.Lineage-tracing mouse model revealed unique developmental regulation of IFN-γ~+Tfh cells,while selective ablation of these cells impaired the induction of Ig G2c~+germinal center B cells and the control of influenza infection.These results indicate that pathogen-associated Tfh cell plasticity is necessary for host immunity,which has implications in vaccine design.展开更多
基金supported by the Innovative Antiviral Therapy Program,Leibniz Institute of Virology(LIV),the German Center for Infection Research(DZIF),EFRE 2014-2020 REACT-EU,Dutch Digestive Fund(MLDS CDG 15-02)Deutsche Forschungsgemeinschaft(BU 3630/2-1)+1 种基金Hüet Roëll Foundation.MK is supported by a Walter Benjamin Fellowship of the Deutsche Forschungsgemeinschaft(KA5554/1-1,KA5554/1-2)The Leibniz Institute of Virology is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health.
文摘Gastrointestinal infections are a major cause for serious clinical complications in infants.The induction of antibody responses by B cells is critical for protective immunity against infections and requires CXCR5+PD-1++CD4+T cells(TFH cells).We investigated the ontogeny of CXCR5+PD-1++CD4+T cells in human intestines.While CXCR5+PD-1++CD4+T cells were absent in fetal intestines,CXCR5+PD-1++CD4+T cells increased after birth and were abundant in infant intestines,resulting in significant higher numbers compared to adults.These findings were supported by scRNAseq analyses,showing increased frequencies of CD4+T cells with a TFH gene signature in infant intestines compared to blood.Co-cultures of autologous infant intestinal CXCR5+PD-1+/−CD4+T cells with B cells further demonstrated that infant intestinal TFH cells were able to effectively promote class switching and antibody production by B cells.Taken together,we demonstrate that functional TFH cells are numerous in infant intestines,making them a promising target for oral pediatric vaccine strategies.
基金the Canadian Instutes of Health Research(CIHR)(FDN-353029,PJT-479040,PJT-479038,FRN-168480(with JDRF),DT4-179512)Genome Canada(GAPP program),the Praespero Foundation,the Alberta Diabetes Foundation,theISClll and FEDER(PIE14/00027,Pl15/0797)+2 种基金Ministerio de Ciencia e Innovacion of Spain(MCINPID2021-125493OB-I00)Generalitat de Catalunya(SGR and CERCA Programmes)and Red Espanola de Supercomputacion(RES,providing CSUC resources).P.Serra was an investigator of the Ramon y Cajal reintegration program and was supported by a JDRF Career Development Award.P.Sole and J.Garnica were supported by predoctoral studentships from FPU(MCIN).
文摘Chronic antigenic stimulation can trigger the differentiation of antigen-experienced CD4+T cells into T regulatory type 1(TR1)cells,a subset of interleukin-10-producing Treg cells that do not express FOxP3.The identities of the progenitor(s)and transcriptional regulators of this T-cell subset remain unclear.Here,we show that the peptide-major histocompatibility complex class Il(pMHCll)monospecific immunoregulatory T-cell pools that arise in vivo in different genetic backgrounds in response to pMHCll-coated nanoparticles(pMHCll-NPs)are invariably comprised of oligoclonal subpools of T follicular helper(TFH)and TR1 cells with a nearly identical clonotypic composition but different functional properties and transcription factor expression profles.Pseudotime analyses of scRNAseq data and multidimensional mass cytometry revealed progressive downregulation and upregulation of TFH and TR1 markers,respectively.Furthermore,pMHCIl-NPs trigger cognate TR1 cell formation in TFH cell-transfused immunodeficient hosts,and T-cell-specific deletion of Bcl6 or Irf4 blunts both the TFH expansion and TR1 formation induced by pMHCl-NPs.In contrast,deletion of Prdm1 selectively abrogates the TFH-to-TR1 conversion.Bcl6 and Prdm1 are also necessary for anti-CD3 mAbinduced TR1 formation.Thus,TFH cells can differentiate into TR1 cells in vivo,and BLIMP1 is a gatekeeper of this cellular reprogramming event.
文摘Follicular helper T (TFH) cells represent a distinct subset of CD4+ helper T (TH) cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile (Bcl6), surface marker expression (CXCR5, PD-1, ICOS and CD4OL) and cytokine production pattern (IL-21 and IL-6). TFH cells provide help to B cells both to form germinal centers (GCs) and to differentiate into memory B cells and plasma cells for generation of humoral responses. However, there is emerging evidence that implicates TFH cells in the development of various human pathologies, such as autoimmune diseases, immunodeficiency and lymphoma. This review focuses on the current progress in this area including mouse and human studies. A clearer understanding of the mechanisms of TFH cell-mediated immunity and pathology may be exploited for rational development of therapeutic strategies. Cellular& Molecular Immunology(2012) 9, 380-385; doi:10.1038/cmi.2012.26; published online 13 August 2012
文摘A fundamental function of T helper(Th)cells is to regulate B-cell proliferation and immunoglobulin class switching,especially in the germinal centers.Th1 and Th2 lineages of CD41 T cells have long been considered to play an essential role in helping B cells by promoting the production immunoglobulin G2a(IgG2a)and IgG1/IgE,respectively.Recently,it has become clear that a subset CD41 T cells,named T follicular helper(Tfh)cells,is critical to B-cell response induction.In this review,we summarize the latest advances in our understanding of the regulation of Tfh cell differentiation,the relationship of Tfh cells to other CD41 T-cell lineages,and the role of Tfh cells in health and disease.
基金This work was supported by VA Merit Award 1I01BX002634,the NIH R21AA022482,R01DK080440,R01DK104656,R01ES025909,R21CA191507,and P30 DK34989(to L.Wang)VA Merit Award 1I01CX000361,NIH U01AA021840,NIH R01 DK107682,NIH R01 AA025208,US DOD W81XWH-12-1-0497(to S.Liangpunsakul),and NIH R21AA024935-01(to L.Wang and S.Liangpunsakul),and NIH R56 AI112398(to A.L.Dent).
文摘Background:Excessive drinkers(ED)and patients with alcoholic liver disease(ALD)are several times more susceptible to bacterial and viral infections and have a decrease in antibody responses to vaccinations.Follicular helper T(TFH)cells are essential to select B cells in the germinal center and to produce antibodies.TFH cells express both a membrane-associated and a soluble form of CD40 ligand(sCD40L),in which the latter form is released to circulation upon T cell activation.The effect of alcohol on TFH cells has not been studied.Objectives:The goals of this study are to determine the levels of TFH and T helper 1(Th1)cells in ED and those with alcoholic cirrhosis(AC)when compared to healthy controls and to determine the prognostic significance of sCD40L in a cohort of patients with AC.Methods:Controls,ED,and those with AC were enrolled.Baseline demographic,laboratory tests,and peripheral blood mononuclear cells(PBMCs)were isolated and assessed via flow cytometry for TFH cells.In vitro study was performed to determine the ability of PBMCs to secrete interferon(IFN)-ɣupon stimulation.Serum sCD40L was also determined and its prognostic significance was tested in a cohort of AC patients.Results:The levels of circulating TFH(cTFH)cells were significantly lower in peripheral blood of subjects with ED and AC compared to controls(P<0.05).IFN-ɣsecretion from PBMCs upon stimulation was also lower in ED and those with cirrhosis.Serum sCD40L was significantly lower in ED and AC when compared to that in controls(P<0.0005).Its level was an independent predictor of mortality.Conclusions:Patients with AC had significantly lower level of cTFH and sCD40L.The level of sCD40L was an independent predictor of mortality in these patients.
基金This work was in part supported by the National Natural Science Foundation of China(81373156,81570587,81401324,81671611)Science and Technology Planning Project of Guangdong Province(2016A020215048,2014A030308005)+1 种基金Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology(2013A061401007)Guangdong Provincial International Cooperation Base of Science and Technology(Organ Transplantation)(2015B050501002),China.
文摘Graft versus host disease(GVHD)is a refractory complication of allogeneic hematopoietic stem cell transplantation for the treatment of malignant and non-malignant hematopoietic diseases.Inflammatory cascade responses and cellular immune reactions are the major factors underlying GVHD pathogenesis.Cells producing the cytokine,interleukin(IL)-21 are crucial players involved in injured tissues in GVHD patients.Besides T helper 17 cells,follicular T helper(Tfh)cells are a new source of IL-21 and play a vital role in GVHD pathogenesis.Tfh cell function is mostly regulated by T-follicular regulatory(Tfr)cells that are also located in the germinal center.This review highlights recent advances in the role of Tfh and Tfr cell function in GVHD pathogenesis.New insights are provided into the potential for clinical application in GVHD prevention and treatment.
基金supported by the National Program on Key Research Project of China (2016YFD0500400 and 2017YFD0501701)the National Natural Science Foundation of China (31872494, 31402176, 31372419, and 31522057)+2 种基金the Fundamental Research Funds for the Central Universities (No. 2662016QD036 to MZ)the Ministry of Science and Technology of China (863 program, No. 2011AA10A212)the Ministry of Agriculture of China (Special Fund for Agro-scientific Research in the Public Interest, No. 201303042 to ZFF)
文摘Rabies is a zoonotic disease that still causes 59,000 human deaths each year,and rabies vaccine is the most effective way to control the disease.Our previous studies suggested that the maturation of DC plays an important role in enhancing the immunogenicity of rabies vaccine.Flt3L has been reported to own the ability to accelerate the DC maturation,therefore,in this study,a recombinant rabies virus expressing mouse Flt3L,designated as LBNSE-Flt3L,was constructed,and its immunogenicity was characterized.It was found that LBNSE-FU3L could enhance the maturation of DC both in vitro and in vivo,and significantly more TFH cells and Germinal Center B(GC B)cells were generated in mice immunized with LBNSE-FU3L than those immunized with the parent virus LBNSE.Consequently,expressing of Flt3L could elevate the level of virus-neutralizing antibodies(VNA)in immunized mice which provides a better protection from a lethal rabies virus challenge.Taken together,our study extends the potential of Flt3L as a good adjuvant to develop novel rabies vaccine by enhancing the VNA production through activating the DC—Tfh^GC B axis in immunized mice.
基金This work was supported by National Natural Science Foundation of China (82002133 and 81600201) Nanjing Medical Science and Technique Development Foundation (QRX17141)Nanjing Department of Health (YKK19056 and YKK19078)+1 种基金Yangzhou Key R&D Program (Social Development) (YZ2020101)Jiangsu Provincial Commission of Health and Family Planning (Q2017003).
文摘B cell-mediated humoral immunity plays a vital role in viral infections,including chronic hepatitis B virus(HBV)infection,which remains a critical global public health issue.Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections,the reduced immune functional capacity of B cells was identified,which was also correlated with chronic hepatitis B(CHB)progression.In addition to B cells,T follicular helper(Tfh)cells,which assist B cells to produce antibodies,might also be involved in the process of anti-HBVspecific antibody production.Here,we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity.Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.
基金supported in part by the National Natural Science Foundation of China(31630022,31821003,31991170 and 31600718)Beijing Municipal Science and Technology Commission(Z181100001318007 and Z171100000417005)。
文摘T follicular helper(Tfh)cells are critical in providing help for B cells in the germinal center reaction.Tfh cell plasticity,especially with regard to their expression of effector Th cytokines,has been described,but lacks in-depth analysis with genetic approaches.In this study,we systemically compared transcriptomic profiles of Tfh cells derived from various types of immune responses and found gene clusters corresponding to effector Th cells were differentially induced in response to pathogens or immune responses.Of special interest,a subset of Tfh cells producing IFN-γwas generated in an influenza virus infection,partially dependent on the innate cytokine IL-12.Lineage-tracing mouse model revealed unique developmental regulation of IFN-γ~+Tfh cells,while selective ablation of these cells impaired the induction of Ig G2c~+germinal center B cells and the control of influenza infection.These results indicate that pathogen-associated Tfh cell plasticity is necessary for host immunity,which has implications in vaccine design.