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Natural Killer Cells

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Natural Killer (NK) cells were initially named based on the observation that they had cytolytic function in the absence of any specific kind of immunization. NK cells can release a bounty of cytokines and chemokines, including TNF-α, IFN-γ, IL-3, IL-10, GM-CSF, G-CSF, CCL2, CCL3, CCL4, CCL5, XCL1, and CXCL8. Type I IFNs, IL-2, IL-12, IL-15, and IL-18 are all potent activators of NK cells. NK cells are a vital arm of innate immunity and participate in surveillance against viral infection and tumor cells.
 

View our: Innate Immunity Pathways

Mechanisms

Mainly derived from the bone marrow, NK cells routinely survey immune cells by checking them for the expression of certain markers. Normal, healthy cells display markers that naturally inhibit NK cell activation. However, upon stress, cells may downregulate markers like MHC I. If an NK cell sees a cell is “missing self” or has an overabundance of NK activating ligands, the NK cell will target that cell for destruction, primarily killing through granzyme and perforin release and FasL-mediated cytotoxicity. In this manner, NK cells help to monitor for viral infection and tumor cells.

 

 

 

Viruses and Cancer

The scanning mechanism of NK cells is what allows them to maintain surveillance for tumor cells and virus-infected cells. Both tumor cells and virus-infected cells can either decrease expression of self markers (i.e., MHC Class I) or overexpress ligands that activate NK cells.

In humans, the major receptors responsible for tumor recognition by NK cells include NKp46, NKp30, NKp44, DNAM-1, and NKG2D. The corresponding ligands of some of these receptors have been identified: MICA/B and the ULBPs for NKG2D; PVR and Nectin-2 for DNAM-1; and B7-H6 for NKp30.

But, viruses and tumor cells can use the NK cell's mechanism against them. Tumors and virus-infected cells have evolved the capability to shed soluble NK cell ligands that serve as decoys. In mice deficient for DNAM-1, NKp46, or NKG2D, tumors altered their expression of ligands (perhaps because they were brazen enough to realize NK cells could not recognize them).
 

To learn more about NK cell cytotoxicity, see this video here.

References:
Vivier, E. et al. 2011. Science. 331:44.

HUMAN NK Cell Target Cell
Inhibitory Receptors CD33 (Siglec-3) Sialic acid
  CD85j (ILT2) HLA Class I
  CD161 (NKR-P1A) LLT-1
  CD305 (LAIR1) Collagen
  CD328 (Siglec-7) Sialic acid
  KIR-L HLA-A, B, C
  KLRG1 (MAFA) Cadherins
  Siglec-9 Sialic acid
     
Inhibitory/Activating Receptors CD94 (NKG2A) HLA-E
  CD244 (2B4) CD48
     
Activating Receptors α4β1 integrin CD106
  β2 integrin (CD18) CD23, CD54, CD102, iC3b
  CD16 IgG
  CD27 CD70
  CD66 CD66
  CD94 (NKG2E) HLA-E
  CD96 (TACTILE) CD155 (PVR)
  CD100 CD72
  CD160 HLA-C
  CD226 (DNAM-1) CD112 (Nectin-2), CD155 (PVR)
  CD314 (NKG2D) ULBP (RAET), MICA/MICB
  CD319 (CRACC) CD319 (CRACC)
  CD335 (NKp46) Viral hemagglutinins, ?
  CD336 (NKp44) Viral hemagglutinins, ?
  CD337 (NKp30) pp65, BAT-3, ?
  CD352 (NTB-A) CD352 (NTB-A)
  CD355 (CRTAM) Necl2
  KIR-S HLA-C, ?
  NKp80 AICL
  PEN-5 CD62L


Adapted from Vivier, E. et al. 2008. Nat. Immunol. 9:503.
Learn more about NK cells on our Cell Markers page.
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MOUSE NK Cell Target Cell
Inhibitory Receptors CD94 (NKG2A) Qa-1
  CD305 (LAIR1) Collagen
  Inhibitory KLRA (Ly49) Receptors MHC Class I
  KLRE-1 ?
  KLRG1 (MAFA) Cadherins
  NKR-P1B (CD161b/NK1.1), NKR-P1D Clr-b (OCIL)
  PILR-α CD99
  Siglec-E Sialic acid
     
Inhibitory/Activating Receptors CD244 CD48
     
Activating Receptors α4β1 integrin CD106
  Activating KLRA (Activating Ly49) Ly49D, Ly49H
  β2 integrin (CD18) CD23, CD54, CD102, iC3b
  CD16 IgG
  CD27 CD70
  CD94-NKG2C Qa-1?
  CD94-NKG2E Qa-1?
  CD223 (LAG-3) MHC Class II
  CD226 (DNAM-1) CD112, CD155 (PVR)
  CD314 (NKG2D) H60, Rae1, MULT-1
  CD319 CD319
  CD335 (NKp46) Viral hemagglutinins, ?
  CD355 (CRTAM) Necl2
  NKR-P1C (CD161c/NK1.1) ?
  NKR-P1A ?
  NKR-P1F Clr-g
  PILR-β CD99


Adapted from Vivier, E. et al. 2008. Nat. Immunol. 9:503.
Learn more about NK cells on our Cell Markers page.
View all NK cell products

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