strategies of nk cell recognition
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
Strategies of NK cell recognition
NO ACTIVATION
PROTECTION
SELFTOLERANCE
Normal cell
MHC class I
Inhibitory KIR/Ly49 Activating receptors+-
Activating ligands
NK cell
« stressed » cell
MHC class I
Inhibitory KIR/Ly49 Activating receptors
Activating ligands
NK cell
ACTIVATION
SENSITIVITY
IMMUNE SURVEILLANCE
+-
Strategies of NK cell recognition
CD16CD16
Act. KIR/Ly49Act. KIR/Ly49
NCRNCR
Some NK cell activating receptors…Some NK cell activating receptors…
Ab-coated targetsAb-coated targets
m157 and what else?m157 and what else?
Virus Hemagglutinins, +?Virus Hemagglutinins, +?
H60, Rae1, MULT1H60, Rae1, MULT1MICA/B, ULBPs MICA/B, ULBPs
NKNK
ITAM-bearing molecules (CD3ITAM-bearing molecules (CD3, FcR, FcR, KARAP/DAP12), KARAP/DAP12)
YxxM-bearing molecules (DAP10)YxxM-bearing molecules (DAP10)
NKG2DNKG2D
1 + 1 + 2 2 integrinsintegrins Adhesion moleculesAdhesion molecules
ECEC TMTM ICIC
DD
DD
ITAMITAM
ITAMITAM
FcRFcR
KARAP/KARAP/DAP12DAP12
Signaling adaptorsSignaling adaptors
DD YxxMYxxMDAP10DAP10
DD ITAMITAM ITAMITAM ITAMITAMCD3CD3
Y x x L x (6-8) Y x x L V V
ITAMITAM(Immunoreceptor Tyrosine-based Activation Motif)(Immunoreceptor Tyrosine-based Activation Motif)
from Vivier & Anfossi, Nature Rev. Immmol. 2004
iNKR
ILT-2CD85jLILRB1
- HRWCCNKKNAVVMDQEPAGNRTVNREDS DEQDPQEVTYAQLNH CVFTQRKIT RPSQRPKTPPTDIIVYTELPNAEP
- SLVYLKKKQVPALPGNPDHREMGETLPEEVGEYRQPSGGSVPVSPGPPSGLEPTSSSPYNPPDLEEAAKTEAENTITYSLLKHPEALDEETEHDYQNHI
FcRIIb
KIR2D
TM
I x Y x x LV VSL
Y x x L x (6-8) Y x x LV V
ITAMITAM(Immunoreceptor Tyrosine-based Activation Motif)(Immunoreceptor Tyrosine-based Activation Motif)
ITIM ITIM (Immunoreceptor Tyrosine-based Inhibition Motif)(Immunoreceptor Tyrosine-based Inhibition Motif)
ITIM-mediated inhibition of NK cell activation
Tyrosine phosphorylation
-
ITIM-bearingreceptor
SHP-1, SHP-2
ITAM-dependentreceptor
+Syk, ZAP70
Cell activation
Syk
* * *
hNKG2DmNKG2D-L
DAP10ITAM-bearing polypeptide(CD3, FcR, KARAP/DAP12)
* * *
CD16NCRKIR-SAct.Ly49CD94-NKG2C/EmNKG2D-S
KIR-LInh. Ly49CD94/NKG2A
KIR-LInh. Ly49CD94/NKG2A
PI3K
PI3,4,5P3
Akt
Sos/RasGRP
Raf Ras
Vav2/3
Rac
PAK1
MEK
ERK
Cytotoxicity Cytokine secretion
+?
Src-family members (e.g. p56lck)
Grb2
SLP-76 LAT Shc
3BP2
Grb2 SLP-76 Vav1 PLC3BP2
PLC
IP3 DAG
Ca2+ PKC
SHP-1SHP-2
SHP-1SHP-2
SHIP
SHIP
Balance of Inhibitory and Stimulatory Recognition Regulates NK Cells
StimulatoryLigands
Self MHC
InhibitoryReceptor
StimulatoryReceptor
+Class I
Normal Cell-protected-
NK Cell
Class I- Transformation/
InfectionClass I -
NK cells lyse cells that lack self MHC class I
IFN-
Class I+Transformation/
InfectionClass I
+
NK cells lyse MHC I+ cells that upregulate stimulatory ligands
IFN-