Nathalie Signoret is a Senior lecturer in Immunology. She obtained her undergraduate and master degrees as well as her PhD in Immunology from the University of Aix- Marseille II (France). During her PhD, she studied the role of the glycoprotein CD4 in HIV infection in the group of Prof. Quentin Sattentau at the Centre d’Immunologie de Marseille-Luminy (CIML). Nathalie then moved to the MRC-LMCB in London for a post-doc with Prof. Mark Marsh where she developed her interest in chemokine receptor biology. She remained in the group of Prof. Marsh at the MRC-cell Biology Unit as a senior research associate until 2005, investigating the molecular mechanisms regulating CXCR4 and CCR5 surface expression and intracellular trafficking. In 2006 Nathalie was appointed lecturer in Immunology at HYMS and established her group in york as part of the IIU.
Chemokines and their receptors have emerged as essential modulators for the trafficking and activation of immune cells, in both homeostatic and inflammatory conditions. Our research aims to establish the role of chemokine receptors in regulating mononuclear phagocyte (i.e. monocytes, macrophages and dendritic cells) function during immune responses.
Our work focuses on how individual receptors influence the behaviour of these cells. We are particularly interested in the cell biological mechanisms mediating chemokine receptor activity and controlling basic cellular functions. Using primary human cells, we aim to identify the molecular pathways involved, as well as the molecular mechanisms regulating these different events. By extending our investigations to in vivo physiological or pathological situations we aim to obtain a better understanding of the process of inflammation, and to identify targets for new anti-inflammatory therapy.
We discovered that modulation of cell surface receptors is a significant mechanism to control the cellular response to chemokine stimulation. We demonstrated that internalisation, intracellular transport, and recycling could regulate the surface expression and function of chemokine receptors, and modulate cell migration.
The lab uses in vitro differentiation of human peripheral blood monocytes as a model system. Projects require application of molecular, cellular, as well as biochemical approaches using a broad range of techniques, including confocal microscopy, RNA interference, GST pull-down and immunological assays.
Recruitment of monocytes to sites of inflammation is critical for the elimination of pathogens. This process is governed by the ability of chemokines secreted by cells in the inflamed tissue, to attract circulating blood monocytes. Once arrived at the source of infection, monocytes arrest and carry out their duties of innate immune cells. Our project aims to elucidate the mechanisms controling chemokine receptor expression and regulation and establish how they influence monocytes in innate immune responses.
Intracellular transport is key to the regulation of chemokine receptors but pathways of internalization, sequestration, recycling or degradations can be both receptor and cell type dependent. In order to better understand the regulation of CCR5 in human macrophages, we examine the constitutive and chemokine-induced intracellular pathways followed by endocytosed CCR5 molecules.
The trafficking of chemokine receptors in cells is tightly regulated by interactions with elements of the intracellular machinery. The goal of this project is to identify new interacting partners implicated in the regulation of CCR2 and CCR5 receptors upon chemokine stimulation and cross-regulation via other surface receptors.
CCR5 has been shown in T cells to cluster at the interface with an interacting antigen-presenting cell (APC) when an “immunological synapse” (IS) is formed. Macrophages are APCs that also express CCR5 on their surface, and we are investigating the behaviour of CCR5 on the macrophage side of ISs with T cells.
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