Arrich, James;
(2021)
Innate Immune Pathways in the Draining Lymph Node.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The draining lymph node (dLN) is the anatomical site in which adaptive immune responses are initiated following vaccination. It is increasingly recognised that the dLN also serves an important innate barrier function and that inflammatory stimuli (including vaccine adjuvants) drive cardinal aspects of the innate immune response within the dLN. The characterisation of these intranodal innate immune processes and their impact upon the concurrently developing adaptive immune response is therefore central to the design of novel vaccines and adjuvants. Neutrophil and monocyte infiltration is a cardinal feature of the innate immune response. This phenomenon is studied within the dLN in the context of two key innate immune pathways; cyclooxygenase-dependent prostanoids and type I interferons. These processes were studied using a murine skin immunisation model following challenge with killed E. coli (KEC), which induced the rapid and sequential infiltration of neutrophils and monocytes into the dLN. These infiltrating myeloid cells were major expressers of cardinal prostanoid synthases (cyclooxygenase-2, microsomal PGE synthase-1 and thromboxane synthase), as well as important interferon-stimulated genes such as CXCL9 and CXCL10. Notably, cyclooxygenase inhibition during their infiltration did not modulate the developing humoral immune response. In contrast, type 1 interferons drove the differential upregulation of CD69 by different lymphocyte subsets and the acute production of interferon-γ by dLN NK cells; processes that play important roles in the retention and activation of T cells. In vitro evidence suggests that these processes are driven by interferon-stimulated monocytes, a hypothesis supported by the markedly increased expression of type I interferon stimulated genes by dLN monocytes in vivo. In conclusion, this thesis highlights the role of infiltrating myeloid cells as unappreciated orchestrators of type I interferon-driven innate immune pathways in the dLN. This finding informs hypotheses that assert that inflammatory monocytes drive Th1 T cell responses in the dLN.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Innate Immune Pathways in the Draining Lymph Node |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10118912 |
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