Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Per...Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.展开更多
The interactions of CD4^(+)T cells and B cells are fundamental for the generation of protective antibody responses,as well as for the development of harmful autoimmune diseases.Recent studies of human tissues and bloo...The interactions of CD4^(+)T cells and B cells are fundamental for the generation of protective antibody responses,as well as for the development of harmful autoimmune diseases.Recent studies of human tissues and blood samples have established a new subset of CD4^(+)B helper T cells named peripheral helper T(Tph)cells.Unlike T follicular helper(Tfh)cells,which interact with B cells within lymphoid organs,Tph cells provide help to B cells within inflamed tissues.Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells.The differentiation mechanism is also partly shared between Tph and Tfh cells in humans,and both Tfh and Tph cells can be found within the same tissues,including cancer tissues.However,Tph cells display features distinct from those of Tfh cells,such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bd-6/Blimp1 ratio.Unlike that of Tfh cells,current evidence shows that the target of Tph cells is limited to memory B cells.In this review,we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases.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
Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune ...Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic.In this study,we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia(FOP)patients who underwent lung surgery and served as controls.We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients.In contrast to the FOP patients,Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients.This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients.In summary,our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity.Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.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
Increased numbers of T follicular helper(Tfh)cells have been implicated in the development of autoimmune diseases including primary Sjögren’s syndrome(pSS),but how the Tfh cell response is regulated during autoi...Increased numbers of T follicular helper(Tfh)cells have been implicated in the development of autoimmune diseases including primary Sjögren’s syndrome(pSS),but how the Tfh cell response is regulated during autoimmune pathogenesis remains largely unclear.Here,we first found negative correlations between IL-10^(+)regulatory B(Breg)cell numbers and Tfh cell responses and disease activity in patients with pSS and mice with experimental Sjögren’s syndrome(ESS).Moreover,we detected high expression of IL-10 receptor on Tfh cells and their precursors in both humans and mice.In culture,IL-10 suppressed human and murine Tfh cell differentiation by promoting STAT5 phosphorylation.By using an adoptive transfer approach and two-photon live imaging,we found significantly increased numbers of Tfh cells with enhanced T cell homing into B cell follicles in the draining cervical lymph nodes of RAG-2−/−mice transferred with IL-10-deficient B cells during ESS development compared with those of RAG-2−/−mice transferred with wild-type B cells.In ESS mice,CD19^(+)CD1d^(hi)CD5^(+)Breg cells with decreased IL-10 production exhibited severely impaired suppressive effects on T cell proliferation.Consistently,CD19^(+)CD24^(+)CD38^(hi) Breg cells from pSS patients showed significantly reduced IL-10 production with defective inhibitory function in the suppression of autologous Tfh cell expansion.Furthermore,the adoptive transfer of IL-10-producing Breg cells markedly suppressed the Tfh cell response and ameliorated ESS progression in ESS mice.Together,these findings demonstrate a critical role for IL-10-producing Breg cells in restraining the effector Tfh cell response during pSS development.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
During viral infection,immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection.CD4^(+)T-cell differentiation sits at the center of this axis.D...During viral infection,immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection.CD4^(+)T-cell differentiation sits at the center of this axis.Differentiation toward T-helper 1(Th1)cells mediates inflammation and pathogen clearance,while T follicular helper(Tfh)cells facilitate germinal center(GC)reactions for the generation of high-affinity antibodies and immune memory.While Th1 and Tfh differentiation occurs in parallel,these CD4^(+)T-cell identities are mutually exclusive,and progression toward these ends is determined via the upregulation of T-bet and Bcl6,respectively.These lineage-defining transcription factors act in concert with multiple networks of transcriptional regulators that tip the T-bet and Bd6 axis in CD4^(+)T-cell progenitors to either a Th1 or Tfh fate.It is now clear that these transcriptional networks are guided by cytokine cues that are not only varied between distinct viral infections but also dynamically altered throughout the duration of infection.Thus,multiple intrinsic and extrinsic factors combine to specify the fate,plasticity,and function of Th1 and Tfh cells during infection.Here,we review the current information on the mode of action of the lineage-defining transcription factors Bcl6 and T-bet and how they act individually and in complex to govern CD4^(+)T-cell ontogeny.Furthermore,we outline the multifaceted transcriptional regulatory networks that act upstream and downstream of Bcl6 and T-bet to tip the differentiation equilibrium toward either a Tfh or Th1 fate and how these are impacted by dynamic inflammatory cues.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
T follicular helper(Tfh)cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection.However,the molecular mechanism controlling Tfh cell differentiation is poorly understoo...T follicular helper(Tfh)cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection.However,the molecular mechanism controlling Tfh cell differentiation is poorly understood.Here,through two mixed bone marrow chimeric experiments,we identified Peli1,a T cell-enriched E3 ubiquitin ligase,as an intrinsic regulator that inhibits Tfh cell differentiation.Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator(ICOS)expression,and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4^(+)T cells.Mechanistically,increased ICOS expression on Peli1-KO CD4^(+)T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2,a transcription factor that inhibits Tfh differentiation.Therefore,reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells.As a consequence,Peli1-deficient CD4^(+)T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models.Collectively,our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfhrelated autoimmunity or infectious diseases.展开更多
Helper T cell(Th)has been identified as a critical immune cell for regulating immune response since 1980s.The type 2 helper Tcell(Th2),characterized by the production of interleukin-4(IL-4),IL-5 and IL-13,plays a crit...Helper T cell(Th)has been identified as a critical immune cell for regulating immune response since 1980s.The type 2 helper Tcell(Th2),characterized by the production of interleukin-4(IL-4),IL-5 and IL-13,plays a critical role in immune response against helminths invading cutaneous or mucosal sites.It also has a functional role in the pathophysiology of allergic diseases such as asthma and allergic diarrhea.Currently,most studies have shed light on Th2 cell function and behavior in specific diseases,such as asthma and helminthes inflammation,but not on Th2 cell itself and its differentiation.Based on different cytokines and specific behavior in recent research,Th2 cell is also regarded as new subtypes of T cell,such as IL-9 secreting T cell(Th9)and CXCR5+T follicular helper cells.Here,we will discuss the latest view of Th2 cell towards their function and the involvement of Th2 cell in diseases.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
基金supported by grants from the National Natural Science Foundation of China(No.82271755,No.81871230)Peking University People's Hospital Scientific Research Development Funds(RZ 2022-06).
文摘Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.
基金supported by the Advanced Research and Development Programs for Medical Innovation(AMED-CREST)from the Japan Agency for Medical Research and Development(AMED,to HU)Grants-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology of Japan(to HY).
文摘The interactions of CD4^(+)T cells and B cells are fundamental for the generation of protective antibody responses,as well as for the development of harmful autoimmune diseases.Recent studies of human tissues and blood samples have established a new subset of CD4^(+)B helper T cells named peripheral helper T(Tph)cells.Unlike T follicular helper(Tfh)cells,which interact with B cells within lymphoid organs,Tph cells provide help to B cells within inflamed tissues.Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells.The differentiation mechanism is also partly shared between Tph and Tfh cells in humans,and both Tfh and Tph cells can be found within the same tissues,including cancer tissues.However,Tph cells display features distinct from those of Tfh cells,such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bd-6/Blimp1 ratio.Unlike that of Tfh cells,current evidence shows that the target of Tph cells is limited to memory B cells.In this review,we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases.
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The study was funded by grants from the Special R&D Program of Ministry of Science and Technology(No.2019YFC1316203)Ministry of Science and Technology(No.2020YFC0844700)Clinical Foundation of Tongji Hospital(No.XXGZBDYJ010).
文摘Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic.In this study,we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia(FOP)patients who underwent lung surgery and served as controls.We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients.In contrast to the FOP patients,Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients.This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients.In summary,our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity.Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.
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.
基金supported by grants from the National Natural Science Foundation of China(81771761 and 91842304)Chinese National Key Technology R&D Program,Ministry of Science and Technology(2017YFC0907601 and 2017YFC0907605)+2 种基金General Research Fund,Hong Kong Research Grants Council(17114515 and 17149716)Hong Kong Croucher Foundation(260960116)Sanming Project of Medicine in Shenzhen(SZSM201512019).
文摘Increased numbers of T follicular helper(Tfh)cells have been implicated in the development of autoimmune diseases including primary Sjögren’s syndrome(pSS),but how the Tfh cell response is regulated during autoimmune pathogenesis remains largely unclear.Here,we first found negative correlations between IL-10^(+)regulatory B(Breg)cell numbers and Tfh cell responses and disease activity in patients with pSS and mice with experimental Sjögren’s syndrome(ESS).Moreover,we detected high expression of IL-10 receptor on Tfh cells and their precursors in both humans and mice.In culture,IL-10 suppressed human and murine Tfh cell differentiation by promoting STAT5 phosphorylation.By using an adoptive transfer approach and two-photon live imaging,we found significantly increased numbers of Tfh cells with enhanced T cell homing into B cell follicles in the draining cervical lymph nodes of RAG-2−/−mice transferred with IL-10-deficient B cells during ESS development compared with those of RAG-2−/−mice transferred with wild-type B cells.In ESS mice,CD19^(+)CD1d^(hi)CD5^(+)Breg cells with decreased IL-10 production exhibited severely impaired suppressive effects on T cell proliferation.Consistently,CD19^(+)CD24^(+)CD38^(hi) Breg cells from pSS patients showed significantly reduced IL-10 production with defective inhibitory function in the suppression of autologous Tfh cell expansion.Furthermore,the adoptive transfer of IL-10-producing Breg cells markedly suppressed the Tfh cell response and ameliorated ESS progression in ESS mice.Together,these findings demonstrate a critical role for IL-10-producing Breg cells in restraining the effector Tfh cell response during pSS development.
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 National Health and Medical Research Council(NHMRC)grants to J.R.G.,an Ideas Grant(GNT1182649)and a Project Grant(GNT1137989)supported by a University of Melbourne research scholarshipsupported by an Australian Research Council Future Fellowship(FT130100708).
文摘During viral infection,immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection.CD4^(+)T-cell differentiation sits at the center of this axis.Differentiation toward T-helper 1(Th1)cells mediates inflammation and pathogen clearance,while T follicular helper(Tfh)cells facilitate germinal center(GC)reactions for the generation of high-affinity antibodies and immune memory.While Th1 and Tfh differentiation occurs in parallel,these CD4^(+)T-cell identities are mutually exclusive,and progression toward these ends is determined via the upregulation of T-bet and Bcl6,respectively.These lineage-defining transcription factors act in concert with multiple networks of transcriptional regulators that tip the T-bet and Bd6 axis in CD4^(+)T-cell progenitors to either a Th1 or Tfh fate.It is now clear that these transcriptional networks are guided by cytokine cues that are not only varied between distinct viral infections but also dynamically altered throughout the duration of infection.Thus,multiple intrinsic and extrinsic factors combine to specify the fate,plasticity,and function of Th1 and Tfh cells during infection.Here,we review the current information on the mode of action of the lineage-defining transcription factors Bcl6 and T-bet and how they act individually and in complex to govern CD4^(+)T-cell ontogeny.Furthermore,we outline the multifaceted transcriptional regulatory networks that act upstream and downstream of Bcl6 and T-bet to tip the differentiation equilibrium toward either a Tfh or Th1 fate and how these are impacted by dynamic inflammatory cues.
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.
基金supported by grants from the National Key R&D Program of China(2018YFA0107201,2018YFA0902703)the National Natural Science Foundation of China(82030041,81770567)+4 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39030300)the Program of Shanghai Academic/Technology Research Leader(20XD1424600)the Key Research Program of the Chinese Academy of Sciences(CAS)(KFZD-SW-216)the Thousand Young Talents Plan of Chinathe CAS Key Laboratory of Tissue Microenvironment and Tumor.
文摘T follicular helper(Tfh)cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection.However,the molecular mechanism controlling Tfh cell differentiation is poorly understood.Here,through two mixed bone marrow chimeric experiments,we identified Peli1,a T cell-enriched E3 ubiquitin ligase,as an intrinsic regulator that inhibits Tfh cell differentiation.Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator(ICOS)expression,and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4^(+)T cells.Mechanistically,increased ICOS expression on Peli1-KO CD4^(+)T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2,a transcription factor that inhibits Tfh differentiation.Therefore,reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells.As a consequence,Peli1-deficient CD4^(+)T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models.Collectively,our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfhrelated autoimmunity or infectious diseases.
文摘Helper T cell(Th)has been identified as a critical immune cell for regulating immune response since 1980s.The type 2 helper Tcell(Th2),characterized by the production of interleukin-4(IL-4),IL-5 and IL-13,plays a critical role in immune response against helminths invading cutaneous or mucosal sites.It also has a functional role in the pathophysiology of allergic diseases such as asthma and allergic diarrhea.Currently,most studies have shed light on Th2 cell function and behavior in specific diseases,such as asthma and helminthes inflammation,but not on Th2 cell itself and its differentiation.Based on different cytokines and specific behavior in recent research,Th2 cell is also regarded as new subtypes of T cell,such as IL-9 secreting T cell(Th9)and CXCR5+T follicular helper cells.Here,we will discuss the latest view of Th2 cell towards their function and the involvement of Th2 cell in diseases.
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.
