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 T cells NK cells Activating and inhibitory receptors Immune evasion by viruses NK licensing PowerPoint Presentation
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 T cells NK cells Activating and inhibitory receptors Immune evasion by viruses NK licensing

 T cells NK cells Activating and inhibitory receptors Immune evasion by viruses NK licensing

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 T cells NK cells Activating and inhibitory receptors Immune evasion by viruses NK licensing

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  1. NK Cells •  T cells • NK cells • Activating and inhibitory receptors • Immune evasion by viruses • NK licensing • NK cell memory • NKT cells

  2. Specialized lymphocytes Immunity DeFranco

  3. IG = 5x1013 compared to αβ TCR = 1018

  4. γδ T cell function • rapid activation (like other innate cells such as NKT, NK etc) • respond to stresses • important at mucosal surfaces • are cytotoxic • secrete IFN-γ and other cytokines • also promote “wound healing” • “knock-out” mice of individual V show effects in tissue where they reside

  5. Form during embryogenesis

  6. Special subsets of γδ T cells • With a select set of V chains • Less diverse joins • Populate distinct tissues

  7. Target cell NK cell Natural killer (NK) cells Target cell Target cell • Do not need prior stimulation for effector function • Lytic function is enhanced when exposed to IFNα, IFNβ or IL-12

  8. Stimulation of NK cells Cytotoxicity and/or cytokines

  9. Function of stimulated NK cells NK cells serve as “speed bumps” in viral infections, by slowing virus production. This allows the slower T cell response to develop and mediate sterilizing immunity (hopefully).

  10. Timing and importance of NK cell response • Make up 5–10% of circulating lymphocytes • Lack specific Ag receptors (no TCR) • Help to regulate innate/adaptive immunity by cytokine secretion • Recognize and destroy pathogen- • infected cells and abnormal tumor cells • Proliferate earlier in infection than CTLs Mice depleted of NK cells succumb to infections such as the Herpesvirus, mouse cytomegalovirus

  11. Rag1 knockout mice • No acquired immunity • Relatively healthy because of NK and other innate cells • Can successfully reproduce • More susceptible to • infections – shorter lifespan

  12. NK cell recognition of target cells NK cells recognize and kill infected and tumor cells by their absence of MHC class I: the missing self model. (a) Normal cells present a ligand for the activating (killing) receptor on NK cells AND a ligand for the inhibitory receptor (class I MHC serves as this second ligand) (b) When viruses infect cells, MHC class I expression is reduced to evade CTLs - This makes them a prime target for elimination by NK cells

  13. NK cell recognition of target cells Activating receptors Inhibitory receptors

  14. Activating receptors for NK cells 1 2 NKp46 NKG2D S sialic acid receptors (eg flu) S stress induced MHC-I related proteins S S -S-S- 3 FcγRIII - use IgG for ADCC

  15. Activating receptors for NK cells NKp46 allows NK cells to recognize cells infected with influenza virus NK NK hemagglutinan Sialic acid on NKp46 Influenza infected cell Influenza infected cell

  16. Activating receptors for NK cells NKG2D A receptor on NK and  T cells that recognizes MIC MIC A non-classical MHC-I induced on epithelial cells after stress such as infection

  17. Activation at epithelium by MIC Epithelial cells MIC NKG2D on NK cell

  18. Viral infections and NK cells Some viruses downregulate MHC-I proteins to evade CTL response virus virus ER Viral protein target cell

  19. NK cell recognition of target cells by “lack of inhibition” Before Infection After Infection KIR (human) Ly49 (mouse) KIR Viral protein ER virus

  20. S Ig S S S S Ig S Ig S S S Ig S S Ig S KIR are polygenic and polymorphic KIR genes KIR = killer cell Ig-like receptors KIR3DL# S Ig S KIR2DL# S S S Ig Ig Ig S S S NK cell 3 S NK cell 1 S Ig Ig S S NK cell 2 Expression of KIR in individual NK cells varies

  21. Ligands for KIR receptors are MHC-I MHC-I is polymorphic and polygenic Classical MHC-I HLA-A, HLA-B, HLA-C

  22. Bare Lymphocyte Syndrome • Deficiency in TAP transporters • MHC Class I not expressed on cell surface • Suffer from increased bacterial lung infections and necrotizing skin lesions • Cause are NK cells because negative signal through KIRs is missing

  23. Combinations of KIR and MHC-1 alleles influence susceptibility to disease DO NOT MEMORIZE

  24. Immune evasion by a murine Herpesvirus MCMV NK Inhibitory receptor for mouse MHC-I (Ly49I) Viral MHC-I homologue virus MCMV MHC-I homologue binds to an inhibitory receptor expressed by certain mouse strains. virus ER Target cell

  25. Resistance to MCMV • But: • some strains of mice completely resistant to MCMV • resistance requires NK cells • MCMV susceptible mouse strains express Ly49I (inhibitory) • MCMV resistant mouse strains express Ly49H (activating)

  26. Resistance to MCMV The activating NK receptor (Ly49H) binds to viral MHC-I homologues NK LY49H allele makes mice resistant to MCMV Activating receptor Viral MHC-I homologue

  27. NK Cells Must be Licenced to Kill • NK cells don’t automatically possess killing potential • It seems they’re “licensed to kill” by a prior interaction with a healthy cell through MHC class I/inhibitory receptor interactions • This gives the “license” only to those NK cells that can exhibit restraint when encountering a healthy, normal cell • Still an area of active research

  28. NK Cell Memory? • Some evidence suggests NK cells can generate a memory response • Very new idea, many questions left to answer • Do all NK cells have capacity to develop into memory cells? • Without Ag receptors, which Ag will trigger memory cell development in NK cells, and how/why?

  29. NKT: hybrid of T and NK cells • Possess a TCR, but it is invariant • Recognizes glycolipids presented by nonpolymorphic CD1d • Can act as helper or killer cells • Killing dependent on Fas-FasL interactions • Include both CD4+ and CD4– cell types • Don’t form memory cells • Possess NK surface proteins rather than those on T cells