调节性T细胞研究进展.ppt

1、,调 节 性 T 细 胞 研 究 进 展 高晓明 北京大学医学部 2009.12.11 苏州,Immunity April，2009,Tr1:Producing IL-10 after Ag triggering NKT:Secret IL-4 after activation Th3:Produce TGF-b after Ag triggering Tact(Anergic T cells)CD8+gd-T cells CD4-CD8-T cells,Other types of regulatory T cells,Treg 细胞的表型,nTreg 和 iTreg,Treg的免疫调节作用

2、机制,Treg的临床应用前景,4,1,2,3,Treg 细胞的表型,Tregs,CD25,Foxp3,TGF-,其他标志分子,Treg与CD25,经典实验 一,Treg与CD25,经典实验 二,Normal mouse,CD4+T cells eliminated CD25+cells,T cell-deficient mouse,Autoimmune diseases Thyroid Stomach Salivary gland Langerhans islets Adrenal glands Ovaries Oestes,CD4+CD25+Tregs在外周淋巴细胞中的比例,Th 9,Th

3、17,性联免疫失调综合征（IPEX）患者,Scurfy小鼠,Foxp3基因敲除小鼠,Treg与Foxp3,2022/10/15,IPEX,Immune deficiency/dysregulationPolyendocrinopathyEnteropathy(Often have Ab against gut epithelium)X-linked inheritance,Patients have mutations in FOXP3 gene.They suffer from inflammatory diseases similar to that seen in mice defici

4、ent in CD4+CD25+Treg cells.,2022/10/15,IPEX Outside(Clinical Findings),First described in 1982 by Powell et al.as a syndrome of diarrhea,polyendocrinopathy,and fatal infection in infancy.Neonatal onset diabetes mellitus Hypothyroidism Enteritis(diarrhea/villous atrophy)Hemolytic anemia&thrombocytope

5、nia.Dermatitis Dermatitis(eczema)Death by 1-2 years of age,2022/10/15,Skin Disease in IPEX,2022/10/15,IPEX Inside(Autopsy Findings),Pancreas:islets of Langerhans absent with lymphocytic infiltratesIntestine:villous atrophy withlyphocytic infiltratesLiver:CholangitisSpleen:enlarged,Lymph nodes:Follic

6、ular hyperplasia Thyroid:Lymphocytic infiltrates Lungs:Consolidation/Inflammation Thymus:Atrophy,(inflammatory diseases similar to that seen in mice deficient in CD4+CD25+nTreg cells).,2022/10/15,FOXP3 Mutations,IPEX syndrome-FOXP3 deficiency,2022/10/15,PROLINE-RICH DOMAIN,ZINC-FINGER,LEUCINEZIPPER,

7、FORKHEAD DOMAIN,N,C,FOXP-3 is the master control gene for Treg development,encodes a novel forkhead/winged helix transcription factor,2022/10/15,What does FOXP3 do?,1 Plays an essential role in the development and function of CD4+CD25+Tregs,Foxp-3 expression in CD4+thymocytes is detected 3 days afte

8、r birth2 May function as a transcriptional repressor of cytokine promoters3 Foxp3 is highly enriched in CD4+CD25+Tregs in thymus as well as in periphery4 Targeted disruption of Foxp3 gene prevents CD4+CD25+nTreg development and mice develop lethal inflammatory disease(Scurfy),Signaling Pathways,Tran

9、scription Factors,and Regulatory DNA Elements that Control Foxp3 Expression.(Josefowicz et al.,Immunity,2009),Treg与TGF-,Nakamura et al.,JEM,2001,CD4+CD25+Tregs高表达TGF-，特别是膜结合型TGF-,Treg与TGF-,TGF-1 缺陷的CD4+CD25+Treg,Wild-type CD4+CD25+T cells,SCID mouse,SCID+colitis mouse,Transfer,动物模型中TGF-对Treg功能的影响,Tr

10、eg与TGF-,TGF-缺陷的CD4+CD25+Treg在体内不能保护小鼠发生自身免疫病性结肠炎,TGF-1 缺陷的CD4+CD25+Treg,Nakamura et al.,JI,2004,wild-type CD4+CD25+T cells,Treg与TGF-,TGF-与CD4+CD25+Treg的诱导产生,Chen et al.,JEM,2003,TGF-and TCRcostimulation induces Foxp3 expression in CD4+CD25-naive responder T cells.,Treg与TGF-,Zhou et al.,Immunity,2009

11、,The Cytokine Milieu Determines CD4+T Cell Differentiation and Conversion,Treg的其他标志分子,CTLA-4,CD39,4,2,Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition.Neuropilin-1 is not a marker of human Foxp3+Treg.,Isolation of functional hu

12、man regulatory T cells(Treg)from the peripheral blood based on the CD39 expression.（J Immunol Methods，2009）,OX40 costimulation can abrogate Foxp3+regulatory T cell-mediated suppression of antitumor immunity.（Int J Cancer，2009）,CTLA-4 control over Foxp3+regulatory T cell function.,小结,Treg的基因表达有其特殊性：信

13、号转导相关基因（COS，SOCS-1，SOCS-2及SLAP130）；分泌性分子（IL-10，IL17，IL-35，MIP-1，MIP-1及ETA-1等）；细胞表面分子（CD2，OX40，CD25，CD122，Ly-6，Thy-1及GITR等）。虽然这些分子中的一些或在一般活化态T细胞表达，或在Foxp3-的无能T细胞表达，但可能正是这样的基因组合保障了Treg的存活和低反应状态，且是其发挥免疫学功能的分子基础。,In thymusIL-2Specific antigen stimulationFoxp-3 expression,2022/10/15,Bone marrow,Deletion,

14、CD25+CD4+,CD4+,CD4+,Periphery,B,Mj,Effector,Thymus,Treg,Nave cells,Self antigen,2022/10/15,IL-2 is required for development of CD4+CD25+nTregs,anti-IL-2 treatment early after birth leads to autoimmune diseases in adults Expansion of nTresgs in thymus is likely autoantigen-driven,2022/10/15,OVA-TCR-t

15、g,OVA-TCR-tg Rag-/-,不表达内源性TCR链,内源性TCR链大量表达,CD4+CD25+nTreg的产生依赖对抗原的特异识别,无CD25 nTregs,产生OVA特异性CD25 nTregs,2022/10/15,Probability of selection,Avidity of TCR-MHC-peptide,Positive selection,Negative selection,CD25+CD4+nTregs,High affinity interaction with MHC/self peptide is required,Naturally occurring

16、 Tregs:CD4+CD25+Foxp3+,Most Foxp3+thymic Treg(tTreg)cells differentiate from Foxp3-negative CD4+SP thymocytes.,CD4+,Foxp3+Treg,Foxp3-,Foxp3-,TE,Tr1,Foxp3+nTreg,Foxp3+iTreg,胸腺,外周,TGF-,IL-10,TGF-b induces the expression of Foxp3 in CD4+CD25-T cells;Retroviral transduction of Foxp3 renders CD4+CD25-T cells suppressiveIL-10 Treatment of CD4+CD25-T cells makes them suppressive,Induction of Tregs 1:,Induction of Tregs 2:,Treg-iTreg（Thsup）,CD25 Treg cells convey a suppressive activity toconventional CD