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

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

4. CD16 Act. KIR/Ly49 NCR Some NK cell activating receptors… Ab-coated targets m157 and what else? Virus Hemagglutinins, +? H60, Rae1, MULT1 MICA/B, ULBPs NK ITAM-bearing molecules (CD3 , FcR , KARAP/DAP12) YxxM-bearing molecules (DAP10) NKG2D  1 +  2 integrins Adhesion molecules

5. ECTMIC D D ITAM ITAM FcR  KARAP/DAP12 Signaling adaptors D YxxM DAP10 D ITAM ITAMITAM CD3 

6. Yxx Lx (6-8) Yxx L V V ITAM (Immunoreceptor Tyrosine-based Activation Motif)

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

8. - HRWCCNKKNAVVMDQEPAGNRTVNREDS DEQDPQE VTYAQL NH CVFTQRKIT RPSQRPKTPPTDI IVYTEL PNAEP - SLVYLKKKQVPALPGNPDHREMGETLPEEVGEYRQPSGGSVPVSPGPPSGLEPTSSSPYNPPDLEEAAKTEAENT ITYSLL KHPEALDEETEHDYQNHI Fc  RIIb KIR2D TM

9. IxYxx LV S L Yxx Lx (6-8) Yxx LV ITAM (Immunoreceptor Tyrosine-based Activation Motif) ITIM (Immunoreceptor Tyrosine-based Inhibition Motif)

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

11. Syk PI3K PI3,4,5P3 Akt Sos/RasGRP Raf Ras Vav2/3 Rac PAK1 MEK ERK CytotoxicityCytokine secretion +? Src-family members (e.g. p56lck) Grb2 SLP-76LAT Shc 3BP2 Grb2 SLP-76 Vav1 PLC  3BP2 PLC  IP3DAG Ca 2+ PKC SHP-1 SHP-2 SHP-1 SHP-2 SHIP

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