1、B細(xì)胞及其新型免疫調(diào)節(jié)功能研究第1頁(yè)，共43頁(yè)。ProliferationAntibodies secretionBCRCD19B-cellT-cellPCCD40L-CD40B-cell is an effector cell第2頁(yè)，共43頁(yè)。 but also a regulatory cellInhibition of CD80, CD86, HLAInhibition of lIL12Induction ofTregInhibition of IFN, TNFnTreg, iTregNKTregBregDCDCT CD4+IL-10CD1dIL-10IL-10, TGFAnergyT

2、CD8+TGF1IL-10T CD4+Inhibition of proliferationIL-10Autoimmune diseasesAntitumor ImmunityTransplantationAllergiesJamin, Arthritis Rheum. 2008Bregs in mice, IL-10 is the key第3頁(yè)，共43頁(yè)。Phenotypes of IL-10 producing Bregs in mice第4頁(yè)，共43頁(yè)。ILBsB2“Innate” Bregs“Immature” Bregs“Adaptive” BregsIgMIL-10BCR/CD40

3、/(TLR)IgMTLRLs/microbesCD40 ligation?ILBsT2-MZPIL-10IL-10T2-MZP?Breg classification?Zhang, CMI, 2013第5頁(yè)，共43頁(yè)。ILBsB2“Innate” Bregs“Immature” Bregs“Adaptive” BregsIgMIL-10BCR/CD40/(TLR)IgMTLRLs/microbesCD40 ligation?ILBsT2-MZPIL-10T2-MZP?Innate-like B cell-derived Bregs?IL-10Breg classificationZhang,

4、CMI, 2013第6頁(yè)，共43頁(yè)。Part I : Innate neonatal Breg in mice and humansPart II : Human B cell project第7頁(yè)，共43頁(yè)。Part I : Innate neonatal Breg in mice and humansPart II : Human B cell project第8頁(yè)，共43頁(yè)。Mouse B cell subset ontogenyHardy et al., 2006CD5+IL-10+Bone marrowLiverB2Marginal zone (MZ) BB1CD5+Conventi

5、onal BInnate-like B第9頁(yè)，共43頁(yè)。IL-10-producing neonatal CD5+ B cells in mice第10頁(yè)，共43頁(yè)。- CD19+ CD19+ CD5+ CD5-In vivo, neonatal CD5+ B cells protect from lethal inflammation第11頁(yè)，共43頁(yè)。CpGTNF-IL-10Neo B subsetsNeo pDC+48 h CD5+ CD5- IL-10-/- pDC: + - + - + - +B cell: -TNF- (pg/ml)IL-10 (ng/ml)Neonatal CD5

6、+ B cell-derived IL-10 controls pDC response following CpG stimulation第12頁(yè)，共43頁(yè)。 CpG+ CTKIL-10Neo B cellspDC-derived type I IFNs enhance IL-10 production by neonatal B cells following CpG stimulation第13頁(yè)，共43頁(yè)。IFN-/Developmental regulation of inflammation第14頁(yè)，共43頁(yè)。? 第15頁(yè)，共43頁(yè)。High percentage of CD5+

7、B cells in cord bloodAduNeoCD45+CD20+CD20+第16頁(yè)，共43頁(yè)。TLR7 TLR9 TLR9Human neonatal B cells produce much higher amount of IL-10 than adult non-memory B cells following TLR stimulations第17頁(yè)，共43頁(yè)。IFN- promotes IL-10 production from B cells following TLR triggeringIFN-a第18頁(yè)，共43頁(yè)。Study the cross-talk betwe

8、en human pDC and B cells第19頁(yè)，共43頁(yè)。pDC enhance the capacity of IL-10 production by B cells following TLR activationIL-10B aloneBpDCFrom pDC+B co-cultureCpGCstimulation第20頁(yè)，共43頁(yè)。Effect of B cells on Th differentiation capacity of pDCpDC48hCpGC+/- aIL-10FACS-sorted pDCAllogenic CD4+ nave T6 daysPMA/Ion

9、omycinICSpDC+B第21頁(yè)，共43頁(yè)。Neonatal B cells negatively control Th1-priming capacity of pDC following CpG stimulation in an IL-10-dependent manner第22頁(yè)，共43頁(yè)。Adu BIs neonatal Breg activity associated with a particular subset ?第23頁(yè)，共43頁(yè)。Is neonatal Breg activity associated with a particular subset ?Innate

10、Breg第24頁(yè)，共43頁(yè)。Neonatal CD5hi B cells inhibit Th1-priming capacity of pDC following CpG stimulationpDC48hCpGCFACS-sorted pDCAllogenic CD4+ nave T6 daysPMA/IonomycinICSpDC+B subsetpDC10+5hi5+5-IFN-g第25頁(yè)，共43頁(yè)。CD43CD27CD9CD44CD10+CD5hiCD5+CD5-ILT3Surface markers of neonatal B subsets第26頁(yè)，共43頁(yè)。Study of B

11、 cell replication historyAdult B cellsNeonatal B cellsInnate Breg第27頁(yè)，共43頁(yè)。Study of B cell VDJ repertoire and CDR3 length第28頁(yè)，共43頁(yè)。CD5hi Bregs have a JH4D6 preference CD10+第29頁(yè)，共43頁(yè)。CD5hi Bregs show an inhibitory signature第30頁(yè)，共43頁(yè)。Neonatal regulation of immune responsesBeneficial?Harmful?BCD5+TLR-L

12、InflammationIL-12TNF-(IL-6.)IFN-/IL-10DCTLR-LpDCcDCMyeloidIL-10Pathogens?Pathogens?IFN-/第31頁(yè)，共43頁(yè)。Part I : Innate neonatal Breg in mice and humansPart II : Human B cell project第32頁(yè)，共43頁(yè)。CD19+PlasmablastB cellSwitched B memoryNon-switched BB immatureIgM+ B memoryB naiveB cell subsets in adult human b

13、lood*: Human B cell immunobiology is largely unexplored*: An integrative view of human B cell subsets will be valuable to decipher their functions第33頁(yè)，共43頁(yè)。IgM/D FITC IgGAE Qdot 655CD19 BV 605CD20 A780CD5 APC CD21 P710 CD24 BV421CD27 PECy7 CD38 A700 CD43 BV510 HLADR BV785 CD70 PC594 CD95 BV711 FcRL4

14、 PE CD3/33/56 PECy5 15-color flow cytometry to define human B cell subsets and their functional statusBD FortessaB LineageDevelopmentFunctional第34頁(yè)，共43頁(yè)。Human B cell subset delineation第35頁(yè)，共43頁(yè)。Study of human B cells in a disease condition第36頁(yè)，共43頁(yè)。Systemic lupus erythematosus, SLESLE affects 70 per

15、 100,000 in China第37頁(yè)，共43頁(yè)。B cellsCD38CD24HDSLE Patient 1SLE Patient 2B cell compartment is severely and diversely disturbed in SLE patients第38頁(yè)，共43頁(yè)。IL-6-producing B cells were greatly increased in active SLE patientsIL-6PMA+Ionomycin stimulationHDActive SLEResolved SLESSCIL-10-producing B cells we

16、re barely detectable第39頁(yè)，共43頁(yè)。IL-6-producing B cells were greatly increased in active SLE patientsPMA+Ionomycin stimulationHDActive SLEResolved SLESwitched memory BIgM+ memory BNave B第40頁(yè)，共43頁(yè)。Ongoing B cell project in SLE patients*: Detailed analysis of B cell phenotypes in different types of SLE patients*: Regulatory functions and underlying mechanism of different B cell subsets*: Identification of novel B cell-related prognostic biomarke