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Strategies of NK cell recognition

Strategies of NK cell recognition. Normal cell. PROTECTION. MHC class I. Activating ligands. NO ACTIVATION. Inhibitory KIR/Ly49. Activating receptors. -. +. SELF TOLERANCE. NK cell. Strategies of NK cell recognition. « stressed » cell. SENSITIVITY. MHC class I.

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Strategies of NK cell recognition

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  1. Strategies of NK cell recognition Normal cell PROTECTION MHC class I Activating ligands NO ACTIVATION Inhibitory KIR/Ly49 Activating receptors - + SELF TOLERANCE NK cell

  2. Strategies of NK cell recognition « stressed » cell SENSITIVITY MHC class I Activating ligands ACTIVATION Inhibitory KIR/Ly49 Activating receptors + - IMMUNE SURVEILLANCE NK cell

  3. Some NK cell activating receptors… b1 + b2 integrins Adhesion molecules CD16 Ab-coated targets Act. KIR/Ly49 m157 and what else? NK NCR Virus Hemagglutinins, +? H60, Rae1, MULT1 MICA/B, ULBPs NKG2D ITAM-bearing molecules (CD3z, FcRg, KARAP/DAP12) YxxM-bearing molecules (DAP10)

  4. Signaling adaptors EC TM IC D FcRg ITAM D CD3z ITAM ITAM ITAM KARAP/ DAP12 D ITAM D DAP10 YxxM

  5. ITAM (Immunoreceptor Tyrosine-based Activation Motif) Y x x L x (6-8) Y x x L V V

  6. iNKR ILT-2 CD85j LILRB1 from Vivier & Anfossi, Nature Rev. Immmol. 2004

  7. TM - HRWCCNKKNAVVMDQEPAGNRTVNREDS DEQDPQEVTYAQLNH CVFTQRKIT RPSQRPKTPPTDIIVYTELPNAEP KIR2D - SLVYLKKKQVPALPGNPDHREMGETLPEEVGEYRQPSGGSVPVSPGPPSGLEPTSSSPYNPPDLEEAAKTEAENTITYSLLKHPEALDEETEHDYQNHI FcgRIIb

  8. ITIM (Immunoreceptor Tyrosine-based Inhibition Motif) I x Y x x L V V S L ITAM (Immunoreceptor Tyrosine-based Activation Motif) Y x x L x (6-8) Y x x L V V

  9. ITIM-mediated inhibition of NK cell activation ITIM-bearing receptor ITAM-dependent receptor SHP-1, SHP-2 Syk, ZAP70 - + Tyrosine phosphorylation Cell activation

  10. CD16 NCR KIR-S Act.Ly49 CD94-NKG2C/E mNKG2D-S KIR-L Inh. Ly49 CD94/NKG2A KIR-L Inh. Ly49 CD94/NKG2A hNKG2D mNKG2D-L * * * * * * ITAM-bearing polypeptide (CD3z, FcRg, KARAP/DAP12) DAP10 SHP-1 SHP-2 SHP-1 SHP-2 Akt Syk SHIP PI3,4,5P3 PI3K Grb2 SLP-76 Vav2/3 Vav1 SLP-76 LAT PLCg 3BP2 Shc Grb2 Rac 3BP2 PLCg SHIP Sos/RasGRP PAK1 Ras Raf MEK IP3 DAG ERK Ca2+ PKC +? Cytotoxicity Cytokine secretion Src-family members (e.g. p56lck)

  11. NK cells lyse MHC I+ cells that upregulate stimulatory ligands NK cells lyse cells that lack self MHC class I IFN-g IFN-g - Transformation/ Transformation/ Class I Infection Infection + Class I - Class I + Class I Balance of Inhibitory and Stimulatory Recognition Regulates NK Cells NK Cell Stimulatory Receptor Inhibitory Receptor Stimulatory Ligands Self MHC + Class I Normal Cell -protected-

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