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Immunological Synapse Formation between T and APC

Immunological Synapse Formation between T and APC. Science 2002 295:1539. Immunological Synapse. APC. TCR. ??. ?. IL-2. Signal Transduction Determines Cell Response. OUTLINE. Role of cytokines in immune system and hematopoiesis Basic concepts of signal transduction

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Immunological Synapse Formation between T and APC

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  1. Immunological Synapse Formation between T and APC Science 2002 295:1539

  2. Immunological Synapse

  3. APC TCR ?? ? IL-2 Signal Transduction Determines Cell Response

  4. OUTLINE • Role of cytokines in immune system and hematopoiesis • Basic concepts of signal transduction • JAK-STAT pathway in cytokine signaling • Regulation of cytokine response • Negative regulators for cytokine signal transduction, SOCS and PIAS families

  5. General Properties of Cytokines • Polypeptides • Produced in response to microbes and antigens • Mediate and regulate immune and inflammatory responses • Pleiotropic and redundant • Regulate the synthesis and actions of other cytokines • Actions are local or systemic (autocrine, paracrine, or endocrine)

  6. Microbes NK NKR TLR IFNg IL-12 DC TLR Macrophage TNFa, IL-1, Chemokines Neutrophils Blood Vessel Cytokines/Chemokines Involved in Innate Immunity Modified from Cell. Mol. Immunol. Abbas & Lichtman 5th Ed. 2003

  7. Cytokines/Chemokines Involved in Innate Immunity Cytokine Producers Targets:Effects TNFa IL-1 IL-12 IFNa/b IFNg Chemokine MØ, DC, T cells Neutrophils: activation Endothelial cells: activation (inflammation) Hypothalamus: Fever Many cells: apoptosis MØ, endothelial Ditto MØ, DC T cells & NK: IFNg synthesis and CTL activity T cells: Th1 differentiation IFNa: MØ All cells: antiviral state, increase MHC I IFNb: fibroblast NK cells: activation NK, NKTMØ: activation (increased microbicidal) T cells, CD8 B cells: isotype switching to IgG2A Many cells: Increase MHC I & MHC II MØ, endothelialLeukocytes: chemotaxis, activation, Fibroblast, T cells migration to tissues Modified from Cell. Mol. Immunol. Abbas & Lichtman 5th Ed. 2003

  8. MHC: peptide T Cell TCR Macrophage DC IL-2 CD4+ T Cell IL2, IFNg IL4, IL5 IL2, IFNg BCR CD8+ B Cell CD8+ CTL Granzyme, Perforin Plasma Cell Ab production How Adaptive Immunity Works Modified from Cell. Mol. Immunol. Abbas & Lichtman 5th Ed.

  9. Cytokines Involved in Adaptive Immunity Cytokine Producers Targets:Effects IL-2 IL-4 IL-5 Lymphotoxin IFNg T cells T cells: proliferation, cytokine production B cells: proliferation, antibody production NK: proliferation and acitvation Th2 B cells: isotype switching to IgE T cells: Th2 differentiation, proliferation Th2 Eosinophils: activation, increase prod B cells: proliferation, IgA production T cells Recruitment and activation of neutrophils Th1, CD8 MØ: activation (increased microbicidal) NK, NKT B cells: isotype switching to IgG2A Many cells: Increase MHC I & MHC II Modified from Cell. Mol. Immunol. Abbas & Lichtman 5th Ed. 2003

  10. Roles of Cytokines in Hematopoiesis Cell. Mol. Immunol. 2003 Abbas & Lichtman 5th ed.

  11. What Happens When Ligands Bind to Receptors • Conformational change of the receptors: • Opens ion channel • Facilitates binding of intracellular signaling proteins such as chemokine receptor • Dimerization (Oligomerization) of the receptors: • Bring signaling molecules into juxtaposition -induces post-translational modification such as phosphorylation in the receptors or signal meidators -activates downstream mediators

  12. Phosphorylation of Proteins as a Controling Mechanism for Signal Transduction Advantages • Rapid: does not require new protein synthesis or protein degradation • Reversible : easily reversed by action of protein phosphatases • Easy to relay signals: phosphorylation on Tyr, Thr, or Ser creating binding sites for other proteins

  13. Tyrosine Phosphorylation Initiates Signaling(In general) PTK Inactive Form Active Form PTP P Signal mediator PTK : Protein Tyrosine Kinase PTP : Protein Tyrosine Phosphatase Note: Src-family kinase

  14. Regulation of Activity of Src Family Kinase Src family: B cells: Lyn, Fyn, Blk T cells: Lck, Fyn, Immunobiology 6th ed. 2005, Janeway et al.

  15. Major Events in Signal Transduction Mediated by Receptor Tyrosine Kinase (RTK) or non-RTK • Ligand-induced receptor dimerization • Activation of kinases • Activation of signal mediators • Activation of transcription factors • Translocation of transcription factors into nucleus and transactivation

  16. Cytokine Receptor-mediated Signaling Pathways

  17. Kinase Signal Transducer P P Activator of Transcription P P P P P P P P Interferon-a Receptor Signaling Pathway IFNR TYK2 JAK1 Cytosol P STAT2 STAT1 STAT3 Nucleus STAT2 STAT1 STAT3 STAT3 GAS STAT1 GAS GAS p48 STAT1 STAT1 STAT3 ISRE

  18. Genetic Approach Biochemical Approach George Stark Cleveland Clinic Fund Ian Kerr ICRF UK Jim Darnell Rockefeller U Sandra Pellegrini David Levy STAT3 Chris Schindler Cloning STAT1 Xin-Yuan Fu STAT2

  19. IFNa or IFNg Analysis promoter of IFN-inducible genes Consensus binding sequence GAS (gamma activated site): TTN 4-6 AA ISRE (IFN-stimulated response element):AGTTN3TTC Purification of ISGF3 or GAF Using GAS or ISRE-column Biochemical Approach for Elucidating IFN Signaling Pathway HeLa Microsequencing and cDNA cloning

  20. ICR191 (frame shift mutagen) Genetic Approach for Elucidating IFN Signaling Pathway Mol. Cell. Biol. 5th ed. 2004 Lodish et al.

  21. Complementation Groups for IFNa (U1-U6) or IFNg (g1 and g2) responses Response to Ligands Complementing Protein Complementation group IFNa/b IFNg - + U1 TYK2 U2 ± ± IRF9(P48) U3 - - STAT1 U4 - - JAK1 U5 - + IFNAR2 U6 - + STAT2 g1 + - IFNGR2 g2 + - JAK2 ± :indicated that some genes do not respond, whereas others do respond well Q: Why there is no STAT3 mutation in the complementation group ? Modified from Science 1994 264:1415

  22. Animation for JAK-STAT signaling

  23. Structural and Functional Domains of JAK Family JAK family : JAK1, JAK2, JAK3 and TYK2 Nat. Rev. Mol. Cell Biol. 2002 3:651

  24. Structural and Functional Domains of STATs STAT family: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 Nat. Rev. Mol. Cell Biol. 2002 3:651

  25. Activation of JAKs and STATs by Cytokines Ligand Jak kinases STATs IFN family Type I IFN- IFNa or IFNb Tyk2, Jak1 STAT1, STAT2 Type II IFN-IFNg Jak1, Jak2 STAT1 gC family IL-2 Jak1, Jak3 STAT5 IL-4 Jak1, Jak3 STAT5 IL-7 Jak1, Jak3 STAT5 gp130 family IL-6 Jak2 STAT3 IL-11 Jak2 STAT3 Modified from Gene 2002 285:1

  26. (wsxws motif for a-helical cytokine) (serpentine) Cytokine Receptor Families by Their Structures

  27. Molecular Structure of Class I Receptors One chain for Ligand Binding One chain for Signal transducing Cytokine Growth Factor Rev 2001 12:19

  28. Critical Roles of gC Family in Lymphocyte Development and Function Nat. Rev. Immunol.2001 1:200

  29. SCID Resulting from Defects in IL-7Ra, JAK3 or gc Chain N. Eng. J. Med. 2000 343:1313

  30. Phenotypes of JAK-Knockout Mice Nat. Rev. Mol. Cell Biol. 2002 3:651

  31. high dose Low dose NHP: non-human primates Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor Science 2003 302:875

  32. Phenotypes of STAT Knockout Mice Nat. Rev. Mol. Cell Biol. 2002 3:651

  33. Impaired Response to IFNa/b and Lethal Viral Disease in Human STAT1 Deficiency Nature Genet. 2003 33:388 (U. Paris)

  34. Negative Regulation of the JAK-STAT pathway • Receptor-mediated endocytosis and degradation • Dephosphorylation by tyrosine phosphatases • Naturally occurring dominant negative STATs such as STAT1b and STAT3b that don’t have transactivating domain • Suppressor of cytokine signaling (SOCS) family • Protein inhibitor of activated Stats (PIAS)

  35. Cell 2002 109:S121-S131

  36. Negative Regulations of Cytokine Signaling Nat. Rev. Immunity 2003 3:900

  37. Structural and Functional Domains of SOCS Family K: Kinase inhibitory region Nat. Rev. Immunol. 2002 2:410

  38. Inhibitory Mechanisms of SOCS Molecules Trend. Immunol. 2003 24:659

  39. SOCS Family Members Target Signaling Proteins for Degradation by Proteasome Trends Biochem. Sci. 2002 27:235

  40. SOCS Targeting Key Signaling Proteins for Degradation by the Proteasome Sci. STKE, Vol. 2003 169:pe6

  41. Liver Degeneration and Lymphoid Deficiencies in Mice Lacking SOCS1 SOCS1-/- SOCS1+/+ Proc. Natl. Acad. Sci. 1998 95: 14395

  42. JBC 2006 281:11135 SOCS1 Is a Critical Inhibitor of IFNgSignaling and Prevents Fatal Neonatal Actions of this Cytokine Cell 1999 98:597

  43. Phenotypes of SOCS Knockout Mice Nat. Rev. Mol. Cell Biol. 2002 3:651

  44. Hypersensitivity of SOCS-1 KO Mice to LPS In Vivo Immunity 2002 Vol. 17:583

  45. SOCS1 Negatively Regulates TLR Signaling by Mal/TIRAP Degradation Forward Nat. Immunol. 2006 7:148

  46. TLR Signaling Pathways back Cell Death Diff. 2006 13:816

  47. SOCS1 Is a Suppressor of Liver Fibrosis and Hepatitis-induced Carcinogenesis JEM 2004 199:1701

  48. Structural and Functional Domains of PIAS Family SIM Nat. Rev. Immunol. 2005 5:593 SAP: Scaffold Attachment factor A and B, Acinus, and PIAS RLD: RING finger-like Zinc binding domain AD: Acidic domain SIM: SUMO- interacting motif S/T: Serine and Threonine-rich

  49. PIAS-protein Regions Involved in Protein–protein Interactions Nat. Rev. Immunol. 2005 5:593

  50. Proposed Mechanisms for Inhibiting the JAK–STAT Pathway by PIAS Proteins Nat. Rev. Immunity 2003 3:900

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