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Investigating the role of lymph node stromal cells and miR-132 in regulating TLR4 agonist adjuvant efficacy

Thuery, Anne LMI (2015) Investigating the role of lymph node stromal cells and miR-132 in regulating TLR4 agonist adjuvant efficacy. PhD thesis, University of York.

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Abstract

Lymph nodes (LNs) are highly organized structures containing adaptive and innate immune cells supported by a network of specialized stromal cells. These stromal cells provide the structural basis for immune cell migration, localization and specialized microenvironments for effector function through the production of specific chemokines. Crosstalk between stroma and haematopoietic cells is important in regulating the efficacy of the immune response in part through their plastic response to inflammation and capacity to generate specialized structures, including germinal centres (GCs). The mechanisms driving tissue remodelling and GC formation in LNs are unclear. Understanding the timing and molecular mechanisms leading to stromal cell reorganization will help generate novel vaccination strategies that can control and regulate immune responses. An adjuvant is a non-antigenic substance that when added to vaccines, enhances the immune response to inoculated antigens. TLR agonists have been shown to be potent second-generation adjuvants. TLR4 agonist adjuvants induce rapid LN remodelling through the loss of B cell follicles and the formation of a ring-like structure in the cortex; surprisingly this was not due to a loss of CXCL13 production by the stromal cells. After forming this ring, large numbers of new B cell follicles appear in the LN paracortex. The molecular mechanisms leading to this reorganization was investigated. TLR4 activation and signalling has to be tightly controlled to avoid uncontrolled inflammation and enable tissue repair. miRNAs constitute a key component in a negative feedback loop in innate immune responses. Deficiency in a TLR4-induced miRNA leads to an altered immune response and changes to adjuvant induced tissue remodelling. By using a simple antigen challenge model, it was possible to determine a novel molecular mechanism controlling LN remodelling and vaccine efficacy.

Item Type: Thesis (PhD)
Academic Units: The University of York > Biology (York)
Depositing User: Miss Anne LMI Thuery
Date Deposited: 24 May 2016 09:41
Last Modified: 24 May 2016 09:41
URI: http://etheses.whiterose.ac.uk/id/eprint/13045

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