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Natural Killer Cells

By Levi Clancy for Student Reader on

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Natural killer cells (NK cells) are part of the innate immune system. Instead of directly recognizing pathogens, natural killer cells monitor cell surface molecules indicative of pathogenesis.

This sensitivity allows natural killer cells to vigorously initiate natural killer cytotoxicity (by emptying granules of porforin and granzyme) and inflammation as soon as pathogenesis is detected, and is essential to protection against viruses and tumors. Natural killer cells have genomic (not needed recombination, or RAG-independent) cell surface receptors which recognize classical Class I MHC molecules (and structural relatives like MICA, RAE-1 and H-60).

Natural killer cells lack TcRs, CD4s and CD8; instead, they have: cell-surface activating receptors, which bind noncovalently to molecules with ITAMs; and on the cytoplasmic side, inhibitory receptors with ITIM(s) which -- upon phosphorylation -- recruit and activate SHP-1 & -2, which inhibit the activating receptors. The balance between activating signals and inhibitory signals is what determines whether a natural killer cell will destroy or bypass a microbe it encounters.

There are many different inhibitory and activating receptors, but two well-studied ones are:
CD94/NKG2AInhibitory ReceptorCD94/NKG2A is a disulfide-linked heterodimer expressed on natural killer cells and some T cells. CD94/NKG2A binds the nonclassical Class I MHC molecule HLA-E (Qa-1 in mice). HLA-E specifically binds HLA-A, -B, -C or -G leader sequences, which inhibits natural killer cells from destroying a cell expressing MHCs. Viruses can stop host cell protein synthesis, thus stopping HLA-E, reducing natural killer cell inhibition and making the host very susceptible to destruction. Also, this feature of CD94/NKG2A inhibits natural killer cells from destroying cells expressing self peptides.
NKG2DActivating ReceptorNKG2D is a homodimeric (NKG2D/NKG2D) activating receptor expressed on natural killer cells and cytotoxic T cells. NKG2D binds MICA and MICB, two non-classical Class I MHC proteins which are expressed by stressed cells and over-expressed by epithelial tumors. Mice have no MICA- nor MICB-like proteins, but weakly homologous murine RAE-1 and H-60 can ligate to NKG2D.