Natural Killer (NK) cells are lymphocytes of the innate immune system. However, there is increasing
evidence that they can also play important roles in the adaptive immune system; as initiators, through
antigen presentation; as effectors, via early release of IFN-y; and as immunoregulators, by eliminating
over-activated macrophages. The functions of NK cells in these roles are intimately linked to their
interactions with other cells during an immune response, for example recognition of target cells via
activating receptors.
The activating receptor NKG2D recognises proteins that are not normally expressed at the surface
of most cells but are up-regulated during a cellular ‘stress’ response. However, NKG2D ligands
can also be induced on human macrophages by TLR stimulation, leading to NK cell-mediated lysis.
Here, I clarify that ligation of TLR4 preferentially up-regulates MICA but not MICB, TLR7/8 ligation
up-regulated both MICA and MICB, while ligating TLR3, signalling through a MyD88-independent
pathway, up-regulated neither. TLR4 stimulation decreased expression of microRNAs, miR-17-5, miR-
20a and miR-93, which target MICA, implicating a novel role for microRNAs in post-transcriptional
regulation of NKG2D ligand expression. Moreover, the pathway involved IL-12/TNF- a-mediated
autocrine signalling, thus incorporating an intrinsic mechanism for NK cell-mediated elimination of
particularly activated macrophages.
In addition to this immunoregulatory role, NK cell activity can shape a subsequent adaptive
immune response. Subsets of NK cells can have distinct functions. Here, I demonstrate that following
culture with IL-2, >25% of human peripheral blood NK cells express HLA-DR, due to an expansion
of a small subset of NK cells expressing HLA-DR, in contrast to previous assumptions that HLADR
is upregulated on previously negative cells. HLA-DR-expressing NK cells exhibited enhanced
degranulation to susceptible target cells and expression of the chemokine receptor CXCR3, which
facilitated their enrichment following exposure to CXCL11/I-TAC. Suggestive of an immunological
role, stimulation of PBMCs with Mycobacterium bovis BCG triggered dramatic expansion of HLADR-
expressing NK cells. In addition, the magnitude of the NK cell IFN-y secretion response in PBMC
triggered by BCG was associated with the proportion of HLA-DR-expressing NK cells ex vivo. A direct
contribution to the immune response was determined by specifically enriching the HLA-DR-expressing
NK cell compartment, which substantially augmented the total NK cell IFN-y secretion response
to BCG. Thus, HLA-DR expression marks a distinct subset of NK cells, present at low frequency
in peripheral blood but readily expanded by IL-2, that can play a significant role during immune
responses.