Millward, Lindsey Jennifer; (2022) Mechanisms of lymph node expansion: the role of MARCKS in fibroblastic reticular cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

During inflammation lymph nodes expand to three to six times their naïve size. This requires extensive tissue remodelling, involving changes to ECM deposition and stromal cell phenotype and number. Fibroblastic reticular cells are a key stromal cell type which form a network within the lymph node paracortex. Following inflammation, migratory dendritic cells enter the lymph node to initiate the adaptive immune response through antigen presentation to T-cells, triggering rapid T-cell proliferation within the paracortex. The fibroblastic reticular cell network maintains integrity and connectivity between neighbours, despite pausing proliferation until after T-cell numbers have doubled, thus withstanding high expansion pressure. Fibroblastic reticular cell network integrity is essential for adaptive immune responses to occur, but the molecular mechanisms controlling lymph node remodelling are poorly understood. In this thesis, I define the morphology of individual fibroblastic reticular cells within the lymph node network, observing for the first time an increased number of fibroblastic reticular cell protrusions forming during acute inflammation. I then delve into the molecular basis of fibroblastic reticular cell protrusions using cultured fibroblastic reticular cells. I interrogated downstream signalling consequences of the interaction between the dendritic cell receptor C-type lectin-like receptor 2 and the fibroblastic reticular cell transmembrane glycoprotein podoplanin, as this interaction has previously been observed to trigger protrusions and elongation of fibroblastic reticular cells in vitro. I identify the neuronal actin regulator Myristoylated Alanine-Rich C-Kinase Substrate as a podoplanin-regulated signalling intermediate with a key role in fibroblastic reticular cell protrusion, a novel finding. Importantly, I reveal that dysregulation of Myristoylated Alanine-Rich C-Kinase Substrate results in a loss of fibroblastic reticular cell network integrity following acute inflammation. Altogether, this thesis provides new insights into the regulatory mechanisms adopted by the lymph node stroma to maintain integrity and thus support a successful adaptive immune response.

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