The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the ear...The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.展开更多
BACKGROUND Advanced glycation end products(AGE)are a marker of various diseases including diabetes,in which they participate to vascular damages such as retinopathy,nephropathy and coronaropathy.Besides those vascular...BACKGROUND Advanced glycation end products(AGE)are a marker of various diseases including diabetes,in which they participate to vascular damages such as retinopathy,nephropathy and coronaropathy.Besides those vascular complications,AGE are involved in altered metabolism in many tissues,including adipose tissue(AT)where they contribute to reduced glucose uptake and attenuation of insulin sensitivity.AGE are known to contribute to type 1 diabetes(T1D)through promotion of interleukin(IL)-17 secreting T helper(Th17)cells.AIM To investigate whether lean adipose-derived stem cells(ASC)could be able to induce IL-17A secretion,with the help of AGE.METHODS As we have recently demonstrated that ASC are involved in Th17 cell promotion when they are harvested from obese AT,we used the same co-culture model to measure the impact of glycated human serum albumin(G-HSA)on human lean ASC interacting with blood mononuclear cells.IL-17A and pro-inflammatory cytokine secretion were measured by ELISA.Receptor of AGE(RAGE)together with intercellular adhesion molecule 1(ICAM-1),human leukocyte Antigen(HLA)-DR,cluster of differentiation(CD)41,and CD62P surface expressions were measured by cytofluorometry.Anti-RAGE specific monoclonal antibody was added to co-cultures in order to evaluate the role of RAGE in IL-17A production.RESULTS Results showed that whereas 1%G-HSA only weakly potentiated the production of IL-17A by T cells interacting with ASC harvested from obese subjects,it markedly increased IL-17A,but also interferon gamma and tumor necrosis factor alpha production in the presence of ASC harvested from lean individuals.This was associated with increased expression of RAGE and HLA-DR molecule by cocultured cells.Moreover,RAGE blockade experiments demonstrated RAGE specific involvement in lean ASC-mediated Th-17 cell activation.Finally,platelet aggregation and ICAM-1,which are known to be induced by AGE,were not involved in these processes.CONCLUSION Thus,our results demonstrated that G-HSA potentiated lean ASC-mediated IL-17A production in AT,suggesting a new mechanism by which AGE could contribute to T1D pathophysiology.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
Background： Immune disorder is an important feature of patients with out-of-hospital cardiac arrest （OHCA） after the return of spontaneous circulation （ROSC）. We investigated the expression of circulatory T helpe...Background： Immune disorder is an important feature of patients with out-of-hospital cardiac arrest （OHCA） after the return of spontaneous circulation （ROSC）. We investigated the expression of circulatory T helper type （Th）1, Th2, and Th 17 cells to explore the early immune alteration in OHCA patients after ROSC. Methods： During July-September 2016 and March-September 2017, 65 consecutive OHCA patients with ROSC 〉 12 h and 30 healthy individuals were enrolled in this study. Clinical and 28-day survival data were collected. Peripheral blood samples were analyzed to evaluate the expression of Th1/Th2/Th 17 cells by flow cytometry from OHCA patients after ROSC on days l and 3 and from healthy individuals. Results： Compared with healthy individuals, T lymphocyte counts and Thl cell counts decreased on days 1 and 3 after ROSC （1464 [1198, 2152] vs. 779 [481, 1140] vs. 581 [324, 1118/μl,χ^2= 30.342, P 〈 0.001; 154 [90, 246] vs. 39 [19, 78] vs. 24 [12, 53]μl, χ^2 = 42.880, P〈 0.001）, and Th2 and Th17 cell counts decreased on day 3 （17.0 [10.8, 24.0] vs. 9.0 [3.0, 15.5]μl, Z= -3.228, P= 0.001; 4.7 [2.7, 9.1] vs. 2.7 [1.0, 6.5]μl, Z = -2.294, P = 0.022）. No change in CD4＋/CD3＋ lymphocyte ratio was seen on day 1 or day 3 （57.9 [49.4, 63.0] vs. 55.4 [46.5, 66.5] vs. 55.4 [50.2, 67.0]%, χ^2 = 0.171, P = 0.918）. Th1/CD4＋ lymphocyte ratio decreased on days 1 and 3 （19.0 [14.0, 24.9] vs. 9.3 [4.6, 13.9] vs. 9.5 [4.9, 13.6]%, χ^2= 25.754, P 〈 0.001）, and Th2/CD4＋ lymphocyte ratio increased on day 1 and decreased on day 3 （1.9 [1.2, 2.5] vs. 2.5 [1.6, 4.0] vs. 1.9 [1.6, 3.81%,χ^2= 6.913, P = 0.032）. Thl/Th2 cell ratio also decreased on both clays （9.4 [7.3, 13.5] vs. 3.1 [1.9, 5.6] vs. 4.2 [2.8, 5.9], χ^2 = 44.262, P 〈 0.001 ）. Despite an upward trend in the median of Th 17/CD4＋ lymphocyte ratio in OHCA patients, there was no significant difference compared with healthy individuals （0.9 [0.4, 1.2] vs. 0.7 [0.4, 1.2] vs. 0.6 [0.3, 1.01%, χ^2= 2.620, P = 0.270）. The dynamic expression of Th1/Th2/Th 17 cells on days 1 and 3 were simultaneously analyzed in 28/53 OHCA patients who survived 〉3 days; patients were divided into survivors （n = 10） and nonsurvivors （n = 18） based on 28-day survival. No significant differences in Th1/Th2/Th 17 cell counts, ratios in CD4＋ lymphocytes, and Th1/Th2 cell ratio were seen between survivors and nonsurvivors on both days （all P 〉 0.05）. There was no difference over time in both survivors and nonsurvivors （all P 〉 0.05）. Conclusion： Downregulated T lymphocyte counts, including Th1/Th2/Th17 subsets and Th1/Th2 cell ratio imbalance, occur in the early period after ROSC, that may be involved in immune dysfunction in OHCA patients.展开更多
基金The National Natural Science Foundation of China,Nos.30871118,30971325,81270129 and 81470268(FL)grants from Department of Science and Technology of Sichuan Province,Nos.09ZQ026-020 and 2009SZ0190(FL)
文摘The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.
文摘BACKGROUND Advanced glycation end products(AGE)are a marker of various diseases including diabetes,in which they participate to vascular damages such as retinopathy,nephropathy and coronaropathy.Besides those vascular complications,AGE are involved in altered metabolism in many tissues,including adipose tissue(AT)where they contribute to reduced glucose uptake and attenuation of insulin sensitivity.AGE are known to contribute to type 1 diabetes(T1D)through promotion of interleukin(IL)-17 secreting T helper(Th17)cells.AIM To investigate whether lean adipose-derived stem cells(ASC)could be able to induce IL-17A secretion,with the help of AGE.METHODS As we have recently demonstrated that ASC are involved in Th17 cell promotion when they are harvested from obese AT,we used the same co-culture model to measure the impact of glycated human serum albumin(G-HSA)on human lean ASC interacting with blood mononuclear cells.IL-17A and pro-inflammatory cytokine secretion were measured by ELISA.Receptor of AGE(RAGE)together with intercellular adhesion molecule 1(ICAM-1),human leukocyte Antigen(HLA)-DR,cluster of differentiation(CD)41,and CD62P surface expressions were measured by cytofluorometry.Anti-RAGE specific monoclonal antibody was added to co-cultures in order to evaluate the role of RAGE in IL-17A production.RESULTS Results showed that whereas 1%G-HSA only weakly potentiated the production of IL-17A by T cells interacting with ASC harvested from obese subjects,it markedly increased IL-17A,but also interferon gamma and tumor necrosis factor alpha production in the presence of ASC harvested from lean individuals.This was associated with increased expression of RAGE and HLA-DR molecule by cocultured cells.Moreover,RAGE blockade experiments demonstrated RAGE specific involvement in lean ASC-mediated Th-17 cell activation.Finally,platelet aggregation and ICAM-1,which are known to be induced by AGE,were not involved in these processes.CONCLUSION Thus,our results demonstrated that G-HSA potentiated lean ASC-mediated IL-17A production in AT,suggesting a new mechanism by which AGE could contribute to T1D pathophysiology.
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This study was supported by grants from the National Natural Science Foundation of China （No. 81372025） and the 2015 Annual Special Cultivation and Development Project for the Technology Innovation Base of the Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation （No. Z151100001615056）.
文摘Background： Immune disorder is an important feature of patients with out-of-hospital cardiac arrest （OHCA） after the return of spontaneous circulation （ROSC）. We investigated the expression of circulatory T helper type （Th）1, Th2, and Th 17 cells to explore the early immune alteration in OHCA patients after ROSC. Methods： During July-September 2016 and March-September 2017, 65 consecutive OHCA patients with ROSC 〉 12 h and 30 healthy individuals were enrolled in this study. Clinical and 28-day survival data were collected. Peripheral blood samples were analyzed to evaluate the expression of Th1/Th2/Th 17 cells by flow cytometry from OHCA patients after ROSC on days l and 3 and from healthy individuals. Results： Compared with healthy individuals, T lymphocyte counts and Thl cell counts decreased on days 1 and 3 after ROSC （1464 [1198, 2152] vs. 779 [481, 1140] vs. 581 [324, 1118/μl,χ^2= 30.342, P 〈 0.001; 154 [90, 246] vs. 39 [19, 78] vs. 24 [12, 53]μl, χ^2 = 42.880, P〈 0.001）, and Th2 and Th17 cell counts decreased on day 3 （17.0 [10.8, 24.0] vs. 9.0 [3.0, 15.5]μl, Z= -3.228, P= 0.001; 4.7 [2.7, 9.1] vs. 2.7 [1.0, 6.5]μl, Z = -2.294, P = 0.022）. No change in CD4＋/CD3＋ lymphocyte ratio was seen on day 1 or day 3 （57.9 [49.4, 63.0] vs. 55.4 [46.5, 66.5] vs. 55.4 [50.2, 67.0]%, χ^2 = 0.171, P = 0.918）. Th1/CD4＋ lymphocyte ratio decreased on days 1 and 3 （19.0 [14.0, 24.9] vs. 9.3 [4.6, 13.9] vs. 9.5 [4.9, 13.6]%, χ^2= 25.754, P 〈 0.001）, and Th2/CD4＋ lymphocyte ratio increased on day 1 and decreased on day 3 （1.9 [1.2, 2.5] vs. 2.5 [1.6, 4.0] vs. 1.9 [1.6, 3.81%,χ^2= 6.913, P = 0.032）. Thl/Th2 cell ratio also decreased on both clays （9.4 [7.3, 13.5] vs. 3.1 [1.9, 5.6] vs. 4.2 [2.8, 5.9], χ^2 = 44.262, P 〈 0.001 ）. Despite an upward trend in the median of Th 17/CD4＋ lymphocyte ratio in OHCA patients, there was no significant difference compared with healthy individuals （0.9 [0.4, 1.2] vs. 0.7 [0.4, 1.2] vs. 0.6 [0.3, 1.01%, χ^2= 2.620, P = 0.270）. The dynamic expression of Th1/Th2/Th 17 cells on days 1 and 3 were simultaneously analyzed in 28/53 OHCA patients who survived 〉3 days; patients were divided into survivors （n = 10） and nonsurvivors （n = 18） based on 28-day survival. No significant differences in Th1/Th2/Th 17 cell counts, ratios in CD4＋ lymphocytes, and Th1/Th2 cell ratio were seen between survivors and nonsurvivors on both days （all P 〉 0.05）. There was no difference over time in both survivors and nonsurvivors （all P 〉 0.05）. Conclusion： Downregulated T lymphocyte counts, including Th1/Th2/Th17 subsets and Th1/Th2 cell ratio imbalance, occur in the early period after ROSC, that may be involved in immune dysfunction in OHCA patients.
