1、T follicular helper (TFH) cellContentHistory IntroductionMolecular characterizationDifferentiationFunctionRegulation Related diseases -taking SLE as an exampleFuture PerspectivesReference Figure 1| T follicular cell helper cellHistoryFigure 1| A timeline of discoveries about T cell help to B cellsA

2、brief history of T cell help to B cells. Crotty - Nat. Rev. Immunol. - March 1, 2015; 15 (3); 185-9Introduction-Heterogeneous subset of CD4+ helper T cells-Present within lymphoid follicles -Critical for germinal center (GC) formation and reactionFollicular B helper T (TFH)cellsMolecular characteriz

3、ationICOSCXCR5Bcl-6IL-21PD-1CD40LCD57Figure 2| T follicular cell helper cellMESQUITA JR, D. et al. Follicular helper T cell in immunity and autoimmunity. Braz J Med Biol Res online. 2016, vol.49, n.5 cited 2016-12-26, e5209.Molecule-B-cell lymphoma 6 (Bcl-6)Master regulator of TFH differentiation in

4、hibiting other T cell subsets dierentiation ； repress the production of Th1, Th2, and Th17 cytokinesbind to DNAsuppress the expression of many microRNAsWithout Bcl-6，TFH differentiation not occur in vivoInduction of CXCR5, ICOS, and PD-1 on CD4+ T cells/wiki/BCL6#/media/File:Protein_BCL6_PDB_1r28.pn

5、gMolecule-CXC Chemokine Receptor 5（CXCR5）Hallmark TFH cell surface markerReceptor for chemokine CXCL13Work when CCR7 expression is lowT cell positioning to follicular GCActivin A plays critical role in regulation Moser B. CXCR5, the Defining Marker for Follicular B Helper T (TFH) Cells.J. Frontiers

6、in Immunology, 2015, 6:296.Figure 3I CXCR5 is required for T cell follicular homing. Figure 4I CXCR5 is required for T cell follicular homing. Figure 5I Down-modulation of CCR7 is required for T cell homing to follicles. Jogdand G M, Mohanty S, Devadas S. Regulators of Tfh Cell DifferentiationJ. Fro

7、ntiers in Immunology, 2016, 7(9).Molecule-Inducible costimulatory (ICOS)Expressed by activated TFH cellsICOSLexpressed by activated B cellsICOSL-ICOS interactiondevelop and maintain TFHformation of GC and memory B cellHuman ICOS deficiencyT cellsBCL-6 、CXCR5 IL-2 receptor Blimp-1 Tfh dierentiationot

8、her eector T cells subsets Molecule-Interleukin-21 (L-21)Important regulator of humoral responses -directly regulating B-cell proliferation and class switching B cellsmature B cellsproliferation，class switching Blimp-1differentiation of B cell into plasma cellsBCL-6develop and maintain the germinal

9、center reactionTFH cellssecrete high levels of IL-21BCL-6 、CXCR5、ICOSDifferentiation- multistage，multifactorial Stage 1: Gneration of pre-TFH Stage 2: Pre-TFHMigration to T-B Border and TFHMaturationStage 3: Germinal center TFH Stage4：TFH functionSawaf M, Dumortier H, Monneaux F. Follicular Helper T

10、 Cells in Systemic Lupus Erythematosus Journal of Immunology Research. 2016;2016:5767106. doi:10.1155/2016/5767106.Figure 6| Generation of pre-TFH Pre-TFH GenerationFigure 7| Generation of pre-TFH Eivazi S, Bagheri S, Hashemzadeh M S, et al. Development of T follicular helper cells and their role in

11、 disease and immune system.J. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2016.Pre-TFH Migration to the T-B BorderSawaf M, Monneaux F. Follicular Helper T Cells in Systemic Lupus Erythematosus Journal of Immunology Research. 2016;2016:5767106. Figure 8| Pre-TFH Migration Guiding

12、pre-TFH into GCFigure 9| Guiding 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 GCGerminal center TFH Figure 10| Germinal

13、 center TFH Life of T follicular helper cells. Suh WK - Mol. Cells - March 1, 2015; 38 (3); 195-201TFH FunctionSawaf, M., Dumortier, H., & Monneaux, F. (2016). Follicular helper t cells in systemic lupus erythematosus: why should they be considered as interesting therapeutic targets?. Journal of Imm

14、unology Research, 2016.Figure 11| TFH Function Function Defranco A L. The germinal center antibody response in health and diseaseJ. F1000research, 2016, 5.Figure 12I Cyclical movement of B cells between the dark zone and light zone of the germinal center (GC).Figure 13(1)| Categories of T cell help

15、to B cells.A brief history of T cell help to B cells. Crotty - Nat. Rev. Immunol. - March 1, 2015; 15 (3); 185-9FunctionsummaryFunctionsummaryFigure 13(2)| 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); 185-9Regula

16、torscytokinessurface receptorstranscription factorsubiquitin ligasemicroRNAFigure 14 | Positive regulatory signaling for Tfh differentiation.Defranco A L. The germinal center antibody response in health and diseaseJ. F1000research, 2016, 5.Figure 15 | Tfh differentiation is tightly negatively regula

17、ted having multiple checkpoints. Defranco A L. The germinal center antibody response in health and diseaseJ. F1000research, 2016, 5.Related diseasesPrimary immunodeficiency eg：X-linked lymphoproliferative diseaseAcquired immunodeficiencyHIVCancer eg：TFHlike lymphomaAutoimmunityFig.16 Role and functi

18、on of TFH cells in immunodeficiency, immune homeostasis, and autoimmunity and levels of potential biomarkers. Scherm, M.G., Ott, V.B. & Daniel, C. Curr Diab Rep (2016) 16: 75. doi:10.1007/s11892-016-0770-2MESQUITA JR, D. et al. Follicular helper T cell in immunity and autoimmunity. Braz J Med Biol R

19、es online. 2016, vol.49, n.5 cited 2016-12-26, e5209.Systemic lupus erythematosus(SLE)Loss of self-tolerance. production of antinuclear auto Ab Affect many internal organsEtiology not well difinedB cells and derivatives (plasma cells) considered at the center of SLE pathogenesis /ency/imagepages/171

20、34.htmFigure 17I Systemic lupus erythematosusEvidence Supporting the Involvement Table 2I Mouse models of autoimmune lupusRigante D and Esposito S, Infections and Systemic Lupus Erythematosus: Binding or Sparring Partners? International journal of molecular sciences, 2015. 16(8): p. 17331-43.Terapeu

21、tic approaches targeting TFH cells in SLEFigure 18: Terapeutic TFH-related targets in SLE: present and future. Example-BenlystaEffective ingredient :BelimumabMechanism: inhibiting recognition by BAFF specifc receptors Side effect: nausea, diarrhea, fever, as well as hypersensitivity and infusion-sit

22、e reactionsDaz-Cerezo S, ngel Mara Garca-Aparicio, Parrondo J, et al. Cost-effectiveness analysis of Belimumab in patients with systemic lupus erythematosus in Spain.J. 2015, 39(n03):161-170.Data on preliminary efficacy, and impact on circulating plasma cells in SLE patientsExample-BenlystaEffective

23、 ingredient :BelimumabMechanism: inhibiting recognition by BAFF specifc receptors Side effect: nausea, diarrhea, fever, as well as hypersensitivity and infusion-site reactionsDaz-Cerezo S, ngel Mara Garca-Aparicio, Parrondo J, et al. Cost-effectiveness analysis of Belimumab in patients with systemic

24、 lupus erythematosus in Spain.J. 2015, 39(n03):161-170.Future PerspectivesHow factors regulate TFH development?Is there division of labor in the GC？Are there functionally different populations of follicular T cells in charge of directing GC B cells to exit the GC as memory or replasma cells, recycle

25、 to the dark zone, or undergo apoptosis ? What are the essential roles and the preferred interacting partners of Tfr cells within the GC？Translation of TFH biology into clinical stratigiesReferenceA brief history of T cell help to B cells. Crotty - Nat. Rev. Immunol. - March 1, 2015; 15 (3); 185-9Sz

26、ab, K., Papp, G., Sznt, A., Tarr, T. and Zeher, M. (2016), A comprehensive investigation on the distribution of circulating follicular T helper cells systemic lupus erythematosus. Clin Exp Immunol, 183: 7689. doi:10.1111/cei.12703MESQUITA JR, D. et al. Follicular helper T cell in immunity and autoim

27、munity. Braz J Med Biol Res online. 2016, vol.49, n.5 cited 2016-12-26, e5209.Sawaf M, Dumortier H, Monneaux F. Follicular Helper T Cells in Systemic Lupus Erythematosus Journal of Immunology Research. 2016;2016:5767106. doi:10.1155/2016/5767106.Locci M, Wu JE, Arumemi F, Mikulski Z, Dahlberg C, Mil

28、ler AT, et al. Activin A programs the dierentiation of human TFH cells. Nat Immunol (2016) 17:97684. doi:10.1038/ni.3494Scherm, M.G., Ott, V.B. & Daniel, C. Curr Diab Rep (2016) 16: 75. doi:10.1007/s11892-016-0770-2Moser B. CXCR5, the Defining Marker for Follicular B Helper T (TFH) Cells.J. Frontiers in Immunology, 2015, 6:296.ReferenceSawaf, M., Dumortier, H., & Monneaux, F