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-