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TCR

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

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TCR

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

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

  3. Immunological Synapse

  4. OUTLINE • Role of cytokines in immune system and hematopoiesis • Basic concepts of signal transduction • JAK-STAT pathway in cytokine signaling • Th1 and Th2 differentiation • 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. Structural and Functional Domains of JAK Family JAK family : JAK1, JAK2, JAK3 and TYK2 Nat. Rev. Mol. Cell Biol. 2002 3:651

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

  19. 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

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

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

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

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

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

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

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

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

  28. Properties of Chemokine and Chemokine Receptors • Chemokines are classified (CC, CXC, CX3C, and XC) based on the number and sequential relationship of the first two of four conserved cysteines • In general, CXC chemokines are critical for acute inflammation, CC chemokines are for chronic inflammation • 50 chemokines 19 chemokine receptors ( human, as of 2006) • Functional redundancy and promiscuity • Interplay of the receptors and ligands can result in agonistic or antagonistic effect • I-TAC> MIG> IP10 (Th1 chemokines, via CXCR3) are antagonist for CCR3 by competing the binding of eotaxin to CCR3

  29. G-Protein Coupled Receptor (GPCR)-mediated Signaling Pathway

  30. Trimeric GTP-binding Proteins (Large G protein) Activation by 7-Transmembrane Receptor (7TM) or GPCR PLC Ca++ Nature Rev. Mol. Cell Biol. 2002 3:639

  31. Differentiation of Immature CD4 Helper T Cells

  32. Figure 10-9 CD4 T-helper Cell Differentiation

  33. Naïve CD4 T Cells can Differentiate into Two Effector Cells

  34. Development of Th1 and Th2 Subsets Cell. Mol. Immunol. 5th ed. Abbas et al.

  35. Effector Functions of Th1 Cells Cell. Mol. Immunol. 5th ed. Abbas et al.

  36. Effector Functions of Th2 Cells Cell. Mol. Immunol. 5th ed. Abbas et al.

  37. Differentiation of T-helper 1 Cells VS T-helper 2 Cells Nat. Rev. Immunol. 2005 5:125

  38. Molecules Involved in Th Differentiation (I)

  39. Molecules Involved in Th Differentiation (II)

  40. Expanding the effector CD4 T-cell repertoire: the Th17 lineage Current Opin. Immunol. 2006 18:349

  41. 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)

  42. Cell 2002 109:S121-S131

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

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

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

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

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

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

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

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

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