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Title: The interactions of human Natural Killer cells with accessory cells
Author: Evans, James Henry
ISNI:       0000 0004 2696 0456
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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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.
Supervisor: Davis, Daniel Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral