Le Bert, N.; (2011) Dendritic cell mediated modulation of immune responses by Mycobacterium vaccae. Doctoral thesis , UCL (University College London).

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Abstract

The contemporary hygiene hypothesis suggests that certain microorganisms that were present throughout human evolution modulate the host immune system to reduce allergy associated T helper 2 (Th2) responses and inflammatory diseases by augmenting regulatory T cells. The prototypic environmental mycobacterium, M. vaccae has been used in mouse models of asthma to support this hypothesis, but data from human models and possible mechanisms are very limited. In view of the role of dendritic cells (DCs) in shaping adaptive T cell responses, the effect of innate immune interactions between human DCs and M. vaccae on allogeneic and antigen specific DC-dependent polarisation of T cells was tested. M. vaccae can stimulate cellular activation via Toll-like receptor 2 (TLR2) and therefore was compared to a specific TLR2 ligand (Pam3CSK4) and alternative stimulation with a TLR4 ligand (LPS). M. vaccae alone induced DC-dependent inhibition of Th2 responses, in contrast to Pam3CSK4, which had the opposite effect and LPS, which had no polarising effect. Comparison of DC maturation, genome-wide transcriptional response, and cytokine production in response to each stimulus did not correlate with the specific functional effects. In particular, directly comparable DC transcriptional responses to M. vaccae and Pam3CSK4 suggested that TLR2-mediated transcriptional regulation was not sufficient for inhibition of Th2 responses. Exclusive transcriptional responses to M. vaccae implicated a role for CREB1-dependent gene expression and analysis of signalling events confirmed selective early activation of the CREB pathway by M. vaccae. Collectively, this work has established that M. vaccae interaction with DCs does inhibit human Th2 responses and that further study of the CREB pathway in this model may provide novel insight into the molecular mechanisms of DC-dependent T cell polarisation. The final chapter of results presents development and validation of a novel approach for using short interspersed elements (SINEs) as a tool for normalisation of RT-qPCR data.

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