Natural Killer Cell Receptors: Human Target Cell – NK Cell Ligand-Receptor Interactions

Click on one of the buttons below to see which receptors in each group activate and which inhibit natural killer cell activity and the ligands that have been identified to date.

HLA-C1
(2DL2/L3)
HLA-C1
(2DL2/L3)
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HLA-C2 (2DL1)
HLA-C2 (2DL1)
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Unknown
Unknown
HLA-BW4 (3DL1)
HLA-BW4 (3DL1)
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HLA-A (3DL2)
HLA-A (3DL2)
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Unknown
Unknown
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HLA-G
HLA-G
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HLA-C (2DS1)
HLA-C (2DS1)
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Unknown
(2DS2-2DS5)
Unknown
(2DS2-2DS5)
Unknown
Unknown
KIR2DL1
KIR2DL2
KIR2DL3
KIR2DL1
KIR2DL2
KIR2DL3
KIR2DL5A
KIR2DL5B
KIR2DL5A
KIR2DL5B
KIR3DL1
KIR3DL2
KIR3DL1
KIR3DL2
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KIR3DL3
KIR3DL3
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KIR2DL4
KIR2DL4
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FcR gamma
FcR gamma
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KIR2DS1
KIR2DS2
KIR2DS3
KIR2DS4
KIR2DS5
KIR2DS1
KIR2DS2
KIR2DS3
KIR2DS4
KIR2DS5
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DAP12
DAP12
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KIR3DS1
KIR3DS1
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DAP12
DAP12
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Inhibiting Receptors
Inhibiting Receptors
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BAG6
BAG6
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Soluble
BAG6
Soluble
BAG6
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BAG6
Exosome
BAG6
Exosome
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B7-H6
B7-H6
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Viral HA
Viral HA
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PCNA
PCNA
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Viral HA
Viral HA
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AICL
AICL
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NKp30
NKp30
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CD3 zeta
CD3 zeta
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FcR gamma
FcR gamma
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NKp44
NKp44
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DAP12
DAP12
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NKp46
NKp46
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CD3 zeta
CD3 zeta
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FcR gamma
FcR gamma
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NKp80
NKp80
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Activating Receptors
Activating Receptors
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HLA-E
HLA-E
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MICA, MICB
MICA, MICB
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ULBP-1-6
ULBP-1-6
CD94-NKG2C/E/H
CD94-NKG2C/E/H
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DAP12
DAP12
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CD94-NKG2A
CD94-NKG2A
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DAP10
DAP10
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NKG2D
NKG2D
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DAP10
DAP10
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Necl-2/IGSF4A
Necl-2/IGSF4A
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CD112/Nectin-2
CD112/Nectin-2
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CD155/PVR
CD155/PVR
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CD112/Nectin-2
CD112/Nectin-2
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CD113/Nectin-3
CD113/Nectin-3
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CD155/PVR
CD155/PVR
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CD111/
Nectin-1
CD111/
Nectin-1
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CRTAM
CRTAM
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DNAM-1/CD226
DNAM-1/CD226
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TIGIT
TIGIT
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CD96
CD96
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2B4/CD244/
SLAMF4
2B4/CD244/
SLAMF4
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NTB-A/
SLAMF6
NTB-A/
SLAMF6
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CRACC/
SLAMF7
CRACC/
SLAMF7
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CD48
CD48
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NTB-A/SLAMF6
NTB-A/SLAMF6
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CRACC/SLAMF7
CRACC/SLAMF7
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CD16/
Fc gamma
RIIIA
CD16/
Fc gamma
RIIIA
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CD3 zeta
CD3 zeta
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FcR gamma
FcR gamma
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CD27
CD27
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CD100/
Semaphorin 4D
CD100/
Semaphorin 4D
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CD160
CD160
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CEACAM-1
CEACAM-1
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ILT2/LILRB1
ILT2/LILRB1
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KLRG1
KLRG1
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LAIR1
LAIR1
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CD161/
NKR-P1A
CD161/
NKR-P1A
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Siglec-3
Siglec-3
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Siglec-7
Siglec-7
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Siglec-9
Siglec-9
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CD27 L/CD70
CD27 L/CD70
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CD72
CD72
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HLA-C
HLA-C
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CEACAM-1
CEACAM-1
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CEACAM-5
CEACAM-5
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HLA Class I
HLA Class I
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E-,N-,R- Cadherins
E-,N-,R- Cadherins
Collagen
Collagen
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OCIL/CLEC2d
OCIL/CLEC2d
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Sialic Acid
Sialic Acid
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IgG
IgG
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Overview of Activating & Inhibitory Natural Killer Cell Receptors

Natural killer (NK) cells are innate lymphocytes that play a crucial role in the early response to infection or malignant transformation. Under these conditions, NK cells are activated and promote target cell death through the release of cytolytic granules. In addition, they secrete cytokines that regulate the functions of other immune cells. The activity of NK cells is controlled by the relative balance of signals received from cell surface receptors that deliver either activating or inhibitory signals. Under normal physiological conditions, NK cell activation is inhibited by ligands expressed on healthy cells that engage inhibitory receptors on NK cells. The reduction in the expression of these ligands occurs in stressed cells and can lead to NK cell activation. NK cells can also be activated by the up-regulation of stress-induced ligands that typically occurs in response to infection or malignant transformation. Due to their ability to specifically attack and eliminate stressed cells, while maintaining tolerance to normal, healthy cells, NK cells are being investigated as potential anti-cancer agents.

NK cells express multiple receptors that are responsible for initiating activating or inhibitory signals. Activating NK cell receptors include members of the human Killer Immunoglobulin-like Receptor (KIR) family or the mouse Ly49 family, CD94-NKG2C/E/H heterodimeric receptors, NKG2D, natural cytotoxicity receptors such as NKp30, NKp44, and NKp46, and the nectin/nectin-like binding receptors DNAM-1/CD226 and CRTAM. In contrast, receptors that inhibit NK cell activation are important for self-tolerance. This group of receptors includes alternate members of the human KIR family or the mouse Ly49 family, CD94-NKG2A, and the nectin/nectin-like binding receptors TIGIT and CD96. In addition to these receptor families, there are multiple other receptors expressed by natural killer (NK) cells that regulate their activation. SLAM family receptors including 2B4/CD244, CRACC/SLAMF7, and NTB-A/SLAMF6, as well as Fc gamma RIIIA/CD16a, CD27, CD100/Semaphorin 4D, and CD160 are additional NK cell activating receptors, while the sialic acid-binding Siglecs (Siglec-3, -7, and -9), ILT2/LILRB1, KLRG1, LAIR-1, CD161/NKR-P1A, and CEACAM-1 are additional NK cell inhibitory receptors. Although ligands for many of these receptors are still being investigated, a variety of viral, tumor cell-associated, and cellular ligands have been identified and are depicted in the schematic.

To learn more, visit our Natural Killer Cell Research Area.

Natural Killer Cell Receptors: Human Target Cell – NK Cell Ligand-Receptor Interactions background image 1