醫(yī)學(xué)免疫學(xué)課件：Tfh細胞的研究進展

1、TFH細胞的研究進展Development of T follicular helper (TFH) cellT follicular helper (TFH) cell IntroductionSignificant moleculesDifferentiationFunctionRelated diseasesFuture PerspectivesIntroductionT follicular helper (TFH) cellsHeterogeneous subset of CD4+ helper T cells present within lymphoid follicles th

2、at are critical in providing signals to B cells in the germinal center reaction. IntroductionFigure 1| A timeline of discoveries about T cell help to B cellsA brief history of T cell help to B cells. Crotty - Nat. Rev. Immunol. - March 1, 2015; 15 (3); 185-9Significant moleculesBcl-6B-cell lymphoma

3、6 (Bcl-6)Master regulator of TFH differentiation Not required for the development of Th1, Th2, or Th17 cells； repress the production of Th1, Th2, and Th17 cytokinesbind to DNAsuppress the expression of many microRNAsWithout Bcl-6，TFH differentiation not occur in vivoB-lymphocyte induced maturation p

4、rotein-1 (Blimp-1) antagonist Significant moleculesCXCR5C-X-C chemokine receptor type 5 (CXCR5)Transmembrane receptor for chemokine CXCL13CXCL13produced in follicles by follicular dendritic cellsB cells enter into follicleTFH cells migrate toward the follicleSignificant moleculesCXCR5Figure 2| CXCR5

5、+ T cells induce antibody production in tonsillar B cells CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B - J. Exp. Med. - December 4, 2000; 192 (11); 1553-62Significant moleculesCXCR5C-

6、X-X chemokine receptor type 5 (CXCR5)Transmembrane receptor for chemokine CXCL13CXCL13produced in follicles by follicular dendritic cellsB cells enter into follicleTFH cells migrate toward the follicleCXCR5+ T cells affect B cell Ig switching (IgM to IgG/IgA) and/or memory B cell activation Signific

7、ant moleculesIL-21Interleukin-21B cellsmature B cellsproliferation，class switching Blimp-1differentiation of B cell into plasma cellsBCL-6develop and maintain the germinal center reactionTFH cellssecrete high levels of IL-21BCL-6 & MAF45Substantial overlap functions （IL-4，IL-6）Significant moleculesI

8、COSInducible costimulator expressed by activated TFH cellsICOSLexpressed by activated B cellsICOSL-ICOS interactiondevelop and maintain TFHformation of GC and memory B cellHuman ICOS deficiencyDifferentiation A multi-stage，multi-factorial processStage 1: generation of pre-TFH Stage 2: guiding pre-TF

9、H into germinal centerStage 3: germinal center TFH Stage 4: generation of potential memory TFH Differentiationgeneration of pre-TFH Figure 3| Generation of pre-TFH Life of T follicular helper cells. Suh WK - Mol. Cells - March 1, 2015; 38 (3); 195-201Differentiationguiding pre-TFH into GCFigure 4| G

10、uiding pre-TFH into GCLife of T follicular helper cells. Suh WK - Mol. Cells - March 1, 2015; 38 (3); 195-201Bystander B cell facilitate the motile behavior of pre-TFH Cognate B cell form stable T-B conjugates move together into the GCDifferentiationgerminal center TFH Figure 5| Germinal center TFH

11、Life of T follicular helper cells. Suh WK - Mol. Cells - March 1, 2015; 38 (3); 195-201Feedforward circuitDifferentiationmemory TFH ?An open questionResting memory TFH cells preferential reactivate TFH program maintain the capacity to become non-TFH cellsMany features of TFH cells are interwined wit

12、h B cellsNot provide significant advantageBiomarkers for vaccine efficacy and progression of autoimmune diseasesFunctionFigure 7| Key events in the germinal center Immunology : a short course seventh edition. Richard Coico, Geoffrey Sunshine. - ISBN 978-1-118-39691-9FunctionFigure 6| The B cell as a

13、n antigen-capture and antigen-presenting cellImmunology : a short course seventh edition. Richard Coico, Geoffrey Sunshine. - ISBN 978-1-118-39691-9FunctionFigure 8| Key interactions involved in TFHB cell cooperation in the germinal centerImmunology : a short course seventh edition. Richard Coico, G

14、eoffrey Sunshine. - ISBN 978-1-118-39691-9 Figure 9(1)| Categories of T cell help to B cells.A brief history of T cell help to B cells. Crotty - Nat. Rev. Immunol. - March 1, 2015; 15 (3); 185-9FunctionsummaryFunctionsummaryFigure 9(2)| Categories of T cell help to B cells.A brief history of T cell

15、help to B cells. Crotty - Nat. Rev. Immunol. - March 1, 2015; 15 (3); 185-9Related diseasesPrimary immunodeficiency eg：X-linked lymphoproliferative diseaseAcquired immunodeficiencyHIVAutoimmunity eg：Myasthenia gravis，Graves disease，Hashimotos thyroiditis，Juvenile dermatomyositis，Systemic lupus eryth

16、ematosus，Sjogrens syndrome，Rheumatoid arthritisCancers eg：TFHlike lymphomaRelated diseasesintroduction of SLESystemic lupus erythematosusAutoimmune chronic inflammatory connective tissue diseaseAntibodies against itself particularly against proteins in the cell nucleusAffect many internal organsCaus

17、ed by unknown environmental triggerNo curetreated with immunosuppressants and corticosteroids to keep symptoms under controlRelated diseasesrole of TFH cells in SLEThe Sanroque mousemutation in roquinhigh-level ICOS and IL-21defective TFH cell function and spontaneous GC formationincrease the autore

18、active B cell responsedecrease the suppressive function of regulatory T cellsHuman SLEaccumulation of TFH cells activation of cognate autoreactive B cellsoveractive GC reactionoverproduction of high-affinity pathogenic autoantibodiesRelated diseasestherapeutic approaches targeting TFH cells in SLEBl

19、ock the action of dendritic cells on CD4 T cells Effector molecules relatively unique to TFH cells ICOSIL-21PD-1Future PerspectivesHow factors regulate TFH development?How TFH features are maintained in the memory phase？Translation of TFH biology into clinical stratigiesReferences1. Basic Immunology

20、: Functions and Disorders of the Immune System. Abul K. Abbas, Andrew H. H. Lichtman, Shiv Pillai - ISBN-13: A brief history of T cell help to B cells. Crotty S - Nat. Rev. Immunol. - March 1, 2015; 15 (3); 185-93. Transcriptional regulation of follicular T-helper (Tfh) cells. Liu X

21、, Nurieva RI, Dong C - Immunol. Rev. - March 1, 2013; 252 (1); 139-454. Follicular helper CD4 T cells (TFH). Crotty S - Annu. Rev. Immunol. - January 1, 2011; 29; 621-635. Cellular and molecular immunology eighth edition. Abul K. Abbas, Andrew H. H. Lichtman, Shiv Pillai - ISBN: 978-0-323-22275-4 6.

22、 CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B - J. Exp. Med. - December 4, 2000; 192 (11); 1553-62References7. Biological effects of IL-21 on different immune cells and its role in autoimmune diseases. Gharibi T, Majidi J, Kazemi T, Dehghanzadeh R, Motallebnezhad M, Babaloo Z Immunobiology - 2016 Feb;221(2):357-678. Life of T follicular helper cells. Suh WK - Mol. Cells - March 1, 2015; 38 (3); 195-2019. T follicular helper cell differentiation, function, and roles in disease.