The symphony of the ninth, Th9 cells, by Dr.Pavulraj.S, veterinary pathologist
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The symphony of the ninth, Th9 cells, by Dr.Pavulraj.S, veterinary pathologist



some information about Th9 cells - subset of T-hepler cells - current and future

some information about Th9 cells - subset of T-hepler cells - current and future



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  • Add all the subsets of T helper cells
  • Write the signature cytokines of Th 1, Th 2 and Th 17
  • Write author name i.e. Paulrajet al., year
  • THIS IS THE MARKERS FOR ANY T HELPER CELLS, I THINK FOR Thelper 9 cells there is no specific markers available to differentiate them from other cells
  • Add title to it
  • Refer the family of IL9 and its receptors
  • Write only author name

The symphony of the ninth, Th9 cells, by Dr.Pavulraj.S, veterinary pathologist The symphony of the ninth, Th9 cells, by Dr.Pavulraj.S, veterinary pathologist Presentation Transcript

  • The symphony of the ninth: the development and function of Th9 cells Pavulraj. S 5246 M.V.Sc., scholar Veterinary pathology
  • Outline of the presentation  Introduction  T-helper cells subsets  Pathway towards Th9 differentiation  Cytokines and transcription factors involved  Function of Th9 cells – IL-9  Role of th9 cells in experimental animal models  Obstacles  Conclusions  Future ……
  • Introduction  CD4+ T helper cells – obligate regulators of inflammatory diseases  There are different subsets of Th cells like Th1, Th2, Th17, Treg, Tfh  Latest addition to the list – Th9  Secrete IL-9 as signature cytokine (Rukhsana Jabeen et al., 2012)
  • Vijay K. Kuchroo Center for neurologic diseases, Brigham and women's hospital, Harvard medical school, Boston
  • T-helper cells subsets  Naïve CD4+ cell (Th) – encounter specific antigen, became differentiate into effectors T helper (Rukhsana Jabeen et al., 2012) subsets  Characterized by distinct pattern of cytokine secretion and function Th1 – (IL-2, IFN-γ) immunity to intracellular pathogens Th2–(IL-4, IL-5, IL-6) protection against extracellular pathogens Th17–(IL-17A, IL-17F, IL-21, IL-22) resistance to bacterial and fungal infection Another effectors subset – Th9 – secrete IL-9, involved in autoimmunity, asthma, etc., (Femke Broere et al., 2011)
  • Th 1 APC T reg Th 2 Naive CD4+ T follicular helper Th 9 Th 17 (Femke Broere et al., 2011)
  •  Ag- activated T cell differentiate in to different phenotype depending on the cytokines in the local environment  Characterized by their cytokine profile and by transcription factors  Eg: IFN-γ and IL-12 Naïve CD4+ Th1 cell secrete IFN-γ, TNF- α, IL-2 (Femke Broere et al., 2011)
  • Pathway towards Th9 differentiation  Naïve Th cells secreting IL-9 are primed in response to cytokines TGF-β and IL-4 are termed as Th9 cells  Both signals are required (Rukhsana Jabeen et al., 2012) TGF-β and IL-4 IL-9
  •  Each cytokine lead to induction of transcription factors that regulate IL-9 production and expression of other genes associated with Th9 phenotypes (Rukhsana Jabeen et al., 2012)  There is no specific marker
  • Th9 cell
  • Role of TGF-β  Transforming growth factor- β  PMN, macrophages are important source  Have role in cell growth, proliferation, differentiation and apoptosis (Veldhoen et al., 2008)  TGF-β signal induce expression of Foxp3 and PU.1 transcription factors (Rukhsana Jabeen et al., 2012)  PU.1 directly bind to Il9 promoter
  • Role of IL-4  Secreted from Th2 cells and mast cells  It activate the transcription factor STAT6 (signal transducer and activator of transcription 6)  STAT-6 indirectly act regulation of additional transcription factors like IRF4, GATA 3  IRF4 bind to Il9 gene (Rukhsana Jabeen et al., 2012)
  •  IL-4 and STAT 6 repress the Foxp3 and T-bet (both induce T-reg phenotype and suppress IL-9 production)  GATA 3 – master regulator of Th2 cell. Not bind to Il9 gene. Have STAT 6 dependent repression of Foxp3 (Rukhsana Jabeen et al., 2012)
  • Other cytokines • IL-25 and IL-1 activate transcription factor NF-κB which bind to Il9 promoter and increase IL-9 production • IFN–γ and IL-27 inhibit IL-9 production in dose dependent manner (Rukhsana Jabeen et al., 2012)
  • Transcription factors for Th9 cells      PU.1 – ETS family transcription factor STAT 6 IRF 4 GATA 3 NF –κB Other cytokines  IL-25  IL-1 (Rukhsana Jabeen et al., 2012)
  • Transcriptional network in T9 cells (Rukhsana Jabeen et al., 2012)
  • PU.1  ETS family transcription factor (E-twenty six) (Hua-Chen Chang et al., 2009)  One of the largest families of transcription factors  Member of this family was identified as a gene transduced by the leukemia virus, E26 (Blair et al., 2000)  Activated by TGF-β  PU.1 is expressed in Th9 cells in higher amounts than in Th2 cells (Rukhsana Jabeen et al., 2012)
  • STAT 6  Signal transducer and activator of transcription 6  In response IL-4, STAT6 phosphorylated by the receptor associated kinases, and then form homo- or hetero-dimers that translocate to the cell nucleus where they act as transcription activators (ShreevratGoenka et al., 2000)
  • IRF 4  Interferon Regulatory Factor 4  Proteins which regulate transcription of interferons  IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)-producing CD4(+) T cell subset Th9  IRF4-deficient CD4(+) T cells failed to develop into IL9-producing Th9 cells  Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells (Marc Veldhoen et al., 2010)
  • GATA 3  Belongs to the GATA family of transcription factors  GATA-3 has been shown to promote the secretion of IL9 from Th9 cells  Not bind to Il9 gene  Cause STAT 6 dependent repression on Foxp3 (Rukhsana Jabeen et al., 2012)
  • NF-κB  Nuclear factor -kappaB  Protein complex that controls transcription of DNA  Resting cell- NF-κB and IκB bounded  On activation IκB destroyed and move to nucleus  Activated by IL-1 (Jacobs, et al., 2012)
  • Il9 gene  Il9 gene is responsible for production of IL-9 from Th9 cells  Location of Il9 gene (Rukhsana Jabeen et al., 2012) Mouse – chromosome 13(40) Human – chromosome 5(46) (Goswami et al., 2011)
  •  Naïve CD4+ T cell from PU.1 deficient mice fail to produce IL-9  Naïve CD4+ T cell from IRF4 deficient mice fail to produce IL-9  Initially it was thought IL-9 produced by Th2 cells, but now it clearly established that it was produced by Th9 cells (Rukhsana Jabeen et al., 2012)
  • Difference between Th2 and Th9 cells Th2 cell  Primed with IL-4  Transcription factors are STAT 6, GATA 3  Producing IL-4, IL-5, IL10, IL-13  Markers are CD119 , CD183, CD193 Th9 cell  Primed with IL-4 and TGF-β  Transcription factors are STAT 6, GATA 3, PU.1, IRF4, NF –κB  Producing IL-9  No specific (Femke Broere et al., 2011)
  • In human  CD4+ T cell acquire Th9 phenotype when differentiate in the presence of TGF-β and IL-4  Other cytokines like IFN-α, IFN-β and IL-21 are potent enhancer of IL-9 production  Blocking IL-21 - ↓IL-9 production  Human T cell require PU.1 and IRF4 for expression of IL-9 (Rukhsana Jabeen et al., 2012)
  • Function of Th9 cells  Th9 cells are pro inflammatory - tending to cause inflammation  Role in broad spectrum of autoimmune disease and allergic inflammation including asthma  Their function is depend on tissue microenvironment and other T-helper cell cytokines (Rukhsana Jabeen et al., 2012)
  • Brief about IL-9  14 kDa peptide  Initially called as P40, Mast cell growth factor  Pleiotropic functions in immune system  Associated with allergy and immunity to extracellular parasites (Goswami et al., 2011)
  • IL-9 receptor signaling  IL-9 activates a heterodimeric receptor that consists of the IL-9 receptor α-chain (IL-9Rα) and the γ-chain and promotes the cross-phosphorylation of Janus kinase 1 (JAK1) and JAK3  This leads to the activation of signal transducer and activator of transcription 1 (STAT1), STAT3 and STAT5 and the upregulation of IL-9-inducible gene transcription (Goswami R, et al., 2011)
  • Receptor sites for IL-9 Function of Th9 cells –IL-9 (Goswami et al., 2011)
  • Th9 role in autoimmune disease models T Cell Transfer Model of Colitis Th9 received mice produce sever colitis, lost weight (Rukhsana Jabeen et al., 2012)
  • Experimental autoimmune encephalitis  MOG specific Th9 received mouse developed sever EAE and lesions in CNS  Cells in the CNS of Th9 recipient retained IL-9 producing capacity  IL-9 has role of growth factor of mast cells  Treatment with anti-IL-9 antibody ameliorate EAE (Rukhsana Jabeen et al., 2012)
  • Role in allergy  IL-9 is highly expressed in the lungs of asthmatic patients  IL-9 production was significantly higher in T cell from atopic infants than non-atopic  In mice – transgenic expression of IL-9 in lungs indicate asthma like response (Rukhsana Jabeen et al., 2012)
  • (Staudt et al., 2010)
  • Allergy cont..  Th9 cell ↑ asthma signs characterized by increase in goblet cell metaplasia, ↑eosinophil infiltration  Anti IL-9 antibody result in amelioration of inflammation (Staudt et al., 2010)
  • Role in parasite expulsion  Experimentally mice was infected with nematode Trichuris muris  When IL-9 given to mice which cause intestinal muscle hyper-contractility, facilitating worm expulsion  Mast cells is target for IL-9 growth factor activity in these nematode infection models, and mast cell mediators cause eosinophilia, mucus production, increased intestinal permeability and contractility, which leads to parasite expulsion (Rukhsana Jabeen et al., 2012)
  • But….. However, the role of Th9 cell may not be universal in all models  Because in adoptive transfer model, Th9 cells specific for hen egg lysozyme, transferred into recipient mice expressing HEL in the eye lens  Even though ocular inflammation was developed, cells recovered from inflamed site produced IFN-γ  Anti-IL-9 did not protect the mice  May be due to flexibility in cytokine production al., 2012) (Rukhsana Jabeen et
  • Pathogenicity of Th9 cells Inflammatory cells entering through the optic nerve head and infiltrating the retina and vitreous Inflammatory cells entering through the limbus and infiltrating the anterior chamber Inflammatory cells in and around an engorged retinal vessel (Cuiyan Tan et al., 2010)
  • IL-9 from bench to bed side  As we know now IL -9 expression is more in asthmatic lung, ragweed pollen and other allergic patients  So, blocking antibodies to IL-9 being developed as therapy for atopic diseases (Goswami et al., 2011)
  • Obstacles  However, the role of Th9 cell may not be universal in all models  Mechanism of Th9 cell contributing autoimmune and allergic inflammation are distinct has not been examined, is focus of ongoing investigations  IL-9 capable of promote inflammation, but Th9 is the source ????? (Rukhsana Jabeen et al., 2012)
  • Conclusions  Th9 develop in response to combined signal from TGF-β and IL-4  Transcription network regulate Th9 development include  TGF- β induced PU.1  IL-4 induced STAT 6 →IRF4, GATA3 & repress Foxp3 and Tbet  IL-9 promote inflammation by stimulating growth of hematopoietic cells esp. mast cells  Th9 cells are capable of promoting autoimmune inflammation
  • Future ……..  But still Th9 & IL-9 has been understudied. Recent advances in defining Th9 and IL-9 will likely promote greater attention  Next steps in the area will be define the orchestration of Th9 cells and direction by Th9 cells in symphony of inflammation
  • References • • Rukhsana, J., and Kaplan, M.H. (2012). The symphony of the ninth: the development and function of Th9 cells. Current Opinion in Immunology, 24: 303–307. • Broere, F., Apasov, S.G., Sitkovsky, M.V. and van Eden, W. (2011). T cell subsets and T cell-mediated immunity. Principles of Immunopharmacology: 3rd revised and extended editon, Springer Basel AG. • Veldhoen, M., Uyttenhove, C., van Snick, J., Helmby, H., Westendorf, A., Buer, J., Martin, B., Wilhelm, C., and Stockinger, B. (2008). Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nature Immunology, 9:1341-1346. • Chang, H., Han, L., Jabeen, R., Carotta, S., Nutt, S.L. and Kaplan, M.K. (2009). PU.1 regulates TCR expression by modulating GATA-3 activity. Journal of Immunology, 183: 4887–4894. • Blair, D.G. and Athanasiou, M. (2000). Ets and retroviruses - transduction and activation of members of the Ets oncogene family in viral oncogenesis. Oncogene, 19: 6472–6481.
  • References cont.. • Goenka, S. and Kaplan, M.H. (2011). Transcriptional regulation by STAT6. Immunologic Research, 50: 87-96. • Veldhoen, M. (2010). Interferon Regulatory Factor 4: Combinational Control of Lymphocyte Differentiation. Journal of Immunology. • Jacobs, M.D. and Harrison, S.C. (1998). Structure of an IκBalpha/NFκB complex. Cell, 95: 749-758. • Goswami R, Kaplan MH: A brief history of IL-9. J Immunol 2011, 186:3283-3288. • Cuiyan Tan, Mehak K. Aziz, Jenna D. Lovaas, Barbara P. Vistica, Antigen-Specific Th9 Cells Exhibit Uniqueness in Their Kinetics of Cytokine Production and Short Retention at the Inflammatory Site, 2010, doi:10.4049/jimmunol • Staudt V, Bothur E, Klein M, Lingnau K, Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells Immunity. 2010 ;33(2):192-202.
  • Thank you for your attention