SIGNAL TRANSDUCTION in IMMUNE SYSTEM

1. SIGNAL TRANSDUCTION in IMMUNE SYSTEM Dr. Gülderen Yanıkkaya Demirel

2. Generic Signalling Pathway Signal Receptor (sensor) Transduction Cascade Targets Response Metabolic Enzyme Cytoskeletal Protein Gene Regulator Altered Metabolism Altered Gene Expression Altered Cell Shape or Motility Adapted from Molecular Biology of the Cell,(2002), 4th edition, Alberts et al.

3. Cell Signaling pathways regulate 􀁺 the cell cycle- proliferation 􀁺 the cytoskeleton- migration 􀁺 transcription- differentiation 􀁺 membrane traffic- exocytosis 􀁺 cell survival and death- apoptosis 􀁺 Development- body plan

6. FORMS of CELL SIGNALING

7. Components of Signalling What are Receptors? Sensors, what the signal/ligand binds to initiate ST Hydrophillic Ligand Cell-Surface Receptor Cell surface Intracellular Plasma membrane Hydrophobic Ligand Carrier Protein Intracellular Receptor Nucleus Adapted from Molecular Biology of the Cell,(2002), 4th edition, Alberts et al.

8. Cell Surface Receptor Types: • Ligand-gated ion channel

9. Cell Surface Receptor Types: 2) G-Protein Coupled Receptor

10. Cell Surface Receptor Types: 3) Enzyme-linked Receptor eg Growth Factor Receptors

11. Generic SignalTransduction

12. INTRACELLULAR SIGNAL CASCADE

13. ST intermediates can be targets for anti-cancer drugs Kinases:Bcr-Abl

15. TCR Signaling and Anergy TCR stimulation in the absence of CD28 signal induces anergy (no proliferation or IL-2 secretion) Associated with increased Cbl leading to degradation of signaling components Assoicated with reduced LAT recruitment and signal transduction (decreased PI3K, GADS-SLP76, Grb2 complex)

16. Inhibiting T cell Activation: Immunosuppresive Therapy Surface directed Antibodies against key components Anti-CD3-T cell depletion: Rx for organ transplant Anti-CD4: T cell depletion: autoimmune disease (psoriasis) and organ transplants CTLA-4 Ig: blocks CD28 engagement; early human trials Altered peptide ligands for tolerization (autoimmunity): MS, allergies

17. Inhibiting T cell Activation: Immunosuppresive Therapy Signaling Calcineurin and NFAT Cyclosporin and tacrolimus (FK506): organ transplants, dermatitis, autoimmune disease, GVHD Complex with cyclophilin or FBP-12, immunophilins that inhibit calcineurin Rapamycin Organ transplants Binds FBP-12 but blocks mTOR, kinase involved in regulating cell growth and proliferation, downstream of IL-2 receptor NF-B inhibition Glucocorticoids (also block AP-1) Experimental drugs as IKK or proteosome inhibitors

18. Aberrant Signaling: Oncogenesis Inappropriate B-or T cell activation can be contribute to oncogenesis (requires additional events) HTLV Tax induces NF-B, ATFs, SRFs, induces IL-2, IL-2R NF-kB mutations in T and B cell lymphomas Lck is T cell oncogene in mice and activated in some human B cell leukemias/lymphomas EBV LMP-1 mimic to CD40 activation, induces sustained B cell activation and transformation through NF-kB, AP-1 and JAK/STAT activation NF-kB activation/mutation in some tumors Zap-70 activation in B-CLL-worse prognosis

19. Defective Signaling: Immunodeficiencies Mutations in signaling components can lead to hereditary immunodeficiencies B cells: BTK deficiency (B cell Tec kinase): Bruton’s X-linked agammaglobulinemia Loss of B cell maturation T cell activation defects Wiskott-Aldrich:WASP deficiency: T cells fail to respond to Ag crosslinking Mutations in CD3 and CD3 Mutations in Zap-70 Failure to synthesize IL-2 NFAT defects X-linked SCID: IL-2R defect

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