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Title: Interactions of natural killer cells, dendritic cells and chemokines in Mycobacterium bovis infection
Author: Siddiqui, Nazneen
ISNI:       0000 0004 2711 9378
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Bovine Tuberculosis (TB), caused by Mycobacterium bovis (M.bovis), has seen a significant rise in incidence in recent years, posing a considerable burden to the UK economy. Protective immunity is associated in part, with rapid IFNγ production and early Th1 polarisation. Natural Killer (NK) cells are known to be a significant source of IFNγ and may therefore play a pivotal role in the innate immune response to mycobacterial infection. This study hypothesised that bovine NK cells participate in the immune response to bovine TB by migrating towards and reciprocally interacting with M.bovis infected dendritic cells (DCs). Bovine NK cells comprise a heterogeneous population characterised by the expression of NKp46 and CD2. Quantitative PCR analyses revealed that blood derived NKp46+ CD2- NK cells transcribed higher levels of important inflammatory and lymphoid homing chemokine receptors and preferentially migrated towards M.bovis infected DCs within in vitro chemotaxis assays when compared with NKp46+ CD2+ NK cells. Furthermore, within co-culture assays, M.bovis infected DCs selectively induced the release of IFNγ from NKp46+ CD2- NK cells with no detectable levels of IFNγ produced by NKp46+ CD2+ cells. This was partially reliant upon IL-12 secreted by M.bovis infected DCs as well as direct cell-cell contact. In addition, NKp46+ CD2- NK cells were able to reciprocally activate infected DCs resulting in up-regulation of cell surface MHC class II. Furthermore, IFNγ expressing NKp46+ CD2- NK cells were detected in the peripheral circulation of cattle as early as two days following experimental infection with M.bovis. This study has provided evidence of reciprocal interactions between CD2- NK cells and mycobacterially infected DCs that could augment both antigen presentation and Th1 biased immune responses. Therefore, this minor blood derived CD2- NK cell subset may be selectively responsible for promoting a protective immune response during the early phases of M.bovis infection and represents a potential target for future vaccination strategies.
Supervisor: Hope, Jayne ; Pease, James ; Coffey, Tracey Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral