IMM334Y.2014 - CYTOKINES IN IMMUNE RESPONSES E.N Fish...

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CYTOKINES IN IMMUNE RESPONSES E.N. Fish E.N. Fish Toronto General Research Toronto General Research Inst. Inst. 67 College Street 67 College Street Room 424 Room 424 e-mail: [email protected] e-mail: [email protected]
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CYTOKINES secreted regulatory proteins influence: survival growth differentiation effector functions in target tissues/cells
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Cytokines in T cell differentiation CYTOKINES: master regulators of the immune system cytokines in inflammation and tissue damage cytokines in hematopoiesis cytokines in immune regulation cytokines in T cell differentiation cytokines in tumor surveillance
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The JAK-STAT Pathway The JAK-STAT Pathway JAK JAK JAK JAK P P P P JAK JAK P P STAT STAT P P P P Y Y S T A T Y S T A T P Y P S T A T Y S T A T P Y P DNA RECEPTOR CYTOPLASM NUCLEUS
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The Jak family comprises four structurally related kinases: Jak1, Jak2, Jak3, and Tyk2 Seven Jak homology regions (JH) containing the catalytically active kinase domain (JH1), the enzymatically inactive pseudokinase domain (JH2), the SH2 domain (JH3, JH4), and a 4.1, ezrin, radixin, moesin (FERM) domain (JH6, JH7) form the Jak protein. The FERM domain mediates Jak binding to the transmembrane cytokine receptor and regulates kinase activity. Schematic structure of Janus family kinases (Jaks)
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SH2 SH2 Linker Linker DNA DNA Coiled-Coil Coiled-Coil TA TA N-term N-term Y701 Y701 Ser Stat1 Stat1 Stat2 Stat2 Stat3 Stat3 Stat4 Stat5a Stat5a Stat5b Stat6 Stat6 851aa 851aa 770aa 770aa 749aa 749aa 793aa 793aa 786aa 786aa 849aa 849aa C 750 750 1 STATs STATs
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STAT Structure N- 134 317 488 576 683 712 Tyrosine Phosphorylation Site -C N-terminal Domain Coiled Coil Domain DNA Binding Domain Linker Domain SH2 Domain Transactivation Domain Chen et al. 1998. Cell 93 :827-39. Becker et al. 1998. Nature 394 :145-51. Crystal Structure of Core Phospho-STAT Bound to DNA N-terminal Domain Structure Solved Separately Vinkemeier et al. 1998. Science 279 :1048-1052. Chen et al. 2003. Protein Science 12 :361-365. Slide courtesy of Dr. James Darnell
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CYTOKINES IN THE ACTIVATION OF…… T cells
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T cell Lineages T cell Lineages Th1 Th2 Treg Suppression regulation Th 17 autoimmunity allergy IFN- γ producing -Intracellular pathogens IL-4, IL-5 producing -Parasitic infection Th9 Th22 IL-22, IL-13, TNF producing - skin pathology IL-9 producing -inflammation allergy
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Th1: intracellular pathogens cellular immunity Th2: extracellular pathogens humoral immunity Th17: secretes IL-17 strong proinflammatory effects The effector T helper cell triad
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APC Ag MHC Class II virus IL-1 IL-12 CD4+ IFN- γ Tc CD8+ MHC Class I IL-2 IL-2R IL-1 IL-4 IL-6 PROLIFERATION TH2 TH1 CD4+ CD4+ PROLIFERATION IL-5 IL-4 IL-3 IL-10 IL-3 IFN- γ TNF TNF IFN- γ - mast cell macrophage / dendritic cell IL-2R THP/TH0 IFN- γ R IL-4R IL-2 IL-2 IL-4 IL-12 IL-18 TLR Costimulatory molecules (I) CD80 / B7.1 (ii) CD86 / B7.2 (iii) CD40 CD28 IL-12Rß2 IL-18R TCR
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T cell lineage T cell lineage commitment The APC is activated by the pathogen , which may be an intracellular organism. surface TLRs recognize the pathogen. TLR activation by pathogen results in e.g. IL-12 production.
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  • Fall '08
  • ABOUHAIDER
  • cells, IL-6, IL-4

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