A joint venture between the Department of Biology and The Hull York Medical School

Profile

Biography

Nathalie Signoret is a 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.

Career

• University of AIX-Marseille II, France
  BSC in Life Sciences 1989
  Master in Immunology 1991
  PhD in Immunology 1996
• MRC-LMCB, London
  Marie Curie Postdoctoral Fellow (1996-1999)
  Postdoctoral Researcher (1999-2001)
• MRC-Cell Biology Unit, London
  Senior Research Associate (2001-2005)
• Centre for Immunology and Infection
  Lecturer in immunology (2006 -)

Research

Overview

Chemokine receptors

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.

Technologies

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.

Current projects

Regulation of CC chemokine receptors on monocytes

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 trafficking of CCR5 in macrophages

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.

CC Chemokine receptors interacting partners

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 from macrophages and the Immnulogical synapse

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.

Research group(s)

• Signoret research group (Immunology)

Available PhD research projects

Role of the chemokine receptor CCR5 during the infection of macrophages by Leishmania parasites (for 2012 - 2013)

It has been shown that Leishmania infection modulates expression of CCR5 on macrophages and that knock-down of this receptor using siRNA in peritoneal macrophages highly reduced parasitic burden in mice, suggesting that this receptor is important for this parasitic infection. However, the mode of action of CCR5 in Leishmania entry into and/or infection of macrophages is unknown. In order to shed some light on these events, we propose to investigate the expression, functional behaviour and intracelluar trafficking properties of CCR5 in murine and human macrophages, comparing steady states conditions and parasitic infection. This project will be carried out in collaboration with the group of Prof. Paul Kaye and will involve primary culture of murine and human blood-isolated cells, plus using immunofluorescence as well as biochemical, molecular biology and RNAi techniques. It will provide training in cellular and molecular cell biology as well as in the field of Host-pathogen interactions.

Please email nathalie.signoret@york.ac.uk for further enquiries.

For application requirements, process, and guidelines please see the postgraduate study pages of the Department of Biology website (http://www.york.ac.uk/biology/postgraduate/). New available studentships are announced on these web pages, the Departmental site and on FindAPhD.

Publications

Selected publications

• Bennett, L.D., Fox, J.M. & Signoret, N. (2011) Mechanisms regulating chemokine receptor activity. Immunology, 134, 246-256.
• Fox, J.M., Lettellier, E., Oliphant, C. and Signoret, N. (2011) TLR2-dependent pathway of heterologous downmodulation for the CC chemokine receptors 1, 2 and 5 in human blood monocytes. Blood. 117(6) 1851-1860.
• Kershaw T, Wavre-Shapton ST, Signoret N, Marsh M. (2009) Analysis of chemokine receptor endocytosis and intracellular trafficking. Methods Enzymol. 460:357-77.
• Signoret N., Hewlett L., Wavre S., Pelchen-Matthews A. Oppermann M. and Marsh M.M. (2005) Agonist-induced endocytosis of CC chemokine receptor 5(CCR5) is clathrin-dependent Mol. Biol. Cell. 16: 902-917.
• Signoret N, Pelchen-Matthews A, Mack M, Proudfoot AE, Marsh M. (2000) Endocytosis and recycling of the HIV coreceptor CCR5. J Cell Biol. 151:1281-94.

Full publications list

• Bennett, L.D., Fox, J.M. & Signoret, N. (2011). Mechanisms regulating chemokine receptor activity. Immunology, 134, 246-256.
• Fox, J.M., Lettellier, E., Oliphant, C. and Signoret, N. (2010) TLR2-dependent pathway of heterologous downmodulation for the CC chemokine receptors 1, 2 and 5 in human blood monocytes. Blood. 117(6) 1851-1860.
• Phillips R. Mattias Svensson1, Naveed Aziz, Asher Maroof, Najmeeyah Brown, Nathalie Signoret, and Paul M. Kaye. (2010) Innate killing of Leishmania donovani by macrophages of the splenic marginal zne requires IRF-7. PLoS Pathog. Mar 12;6(3):e1000813
• Kershaw T, Wavre-Shapton ST, Signoret N, Marsh M. (2009) Analysis of chemokine receptor endocytosis and intracellular trafficking. Methods Enzymol. 460:357-77.
• Smalley MJ, Signoret N, Robertson D, Tilley A, Hann A, Ewan K, Ding Y, Paterson H, Dale TC. (2005) Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta. J. Cell. Sci. 118:5279-5289
• Signoret N., Hewlett L., Wavre S., Pelchen-Matthews A., Oppermann M., and Marsh M. (2005) Agonist-induced endocytosis of CC chemokine receptor 5 (CCR5) is clathrin-dependent. Mol. Biol. Cell 16: 902-917.
• Signoret N., Christophe T., Oppermann M. and Marsh M. (2004) pH-independent endocytic cycling of the chemokine receptor CCR5. Traffic 5: p. 529-543.
• Signoret N., Pelchen-Matthews A., Mack M., Proudfoot A.E. and Marsh M. (2000) Endocytosis and recycling of the HIV coreceptor CCR5. J Cell Biol. 151:1281-94.
• Signoret N. and Marsh M. (2000) Analysis of chemokine receptor endocytosis and recycling. Methods in Molecular Biology. Humana Press, edited by Proudfoot A. E. I., Wells T. N., and Power C. A. 138: 197-207.
• Klasse PJ., Rosenkilde M., Signoret N., Pelchen-Matthews A., Schwartz T. and Marsh M. (1999) Hybrids between CD4 and CXCR4 simulate receptor-coreceptor complexes and mediate X4 HIV-1 infection with reduced sensitivity to block by SDF-1. J. Virol 73 (9): p. 7453-7466.
• Guinamard R., Signoret N., Masamichi I., Marsh M., Kurosaki T. and Ravetch JV. (1999) B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1 alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4. J Exp Med, 189(9): p. 1461-1466.
• Pelchen-Matthews A., Signoret N., Klasse PJ., Fraile-Ramos A., and Marsh M. (1999) Chemokine receptor trafficking and viral replication. Immunol Rev 168: p. 33-49.
• Pelchen-Matthews A., DaSilva R., Bijlmakers M-J., Signoret N., Gordon S. and Marsh M. (1998) Lack of p56lck expression correlated with CD4 endocytosis in primary lymphoid and myeloid cells. Eur. J. Immunol. 28: 3639-3647.
• Signoret N., Rosenkilde M. M., Klasse P.J., Schwartz T. W., Malim M. H., Hoxie J. A and Marsh M. (1998) Differential regulation of CXCR4 and CCR5 endocytosis. J. Cell. Science 111: 2819-2830
• Mack M., B. Luckow, P. J. Nelson, J. Cihak, G. Simmons, P. R. Clapham, N. Signoret, M. Marsh, M. Stangassinger, F.Borlat, T. N.C. Wells, D.Schlundorff, and A. E.I. Proudfoot. (1998) Aminooxypentane-RANTES Induces CCR5 Internalization but Inhibits Recycling: A Novel Inhibitory Mechanism of HIV Infectivity. J. Exp. Med. 187: 1215-1224.
• Signoret N., J. Oldridge, A. Pelchen-Matthews, P.J. Klasse, T. Tran, L.F. Brass, M.M. Rosenkilde, T.W. Schwartz, W. Holmes, W. Dallas, M.A. Luther, T. N. C. Wells, J.A. Hoxie and M. Marsh. (1997) Phorbol esters and SDF-1 induce rapid endocytosis and down-modulation of the chemokine receptor CXCR4. J. Cell Biol. 139, 651-664.
• Simon J. H. M., Stumbles P., Signoret N., Somoza C., Puklavec M., Sattentau Q. J., Barclay N. A. and James W. (1997) Role of CD4 epitopes outside the gp120-binding site during entry of HIV-1. J. Virol. 71, 1476-1484.
• Briant L., Signoret N., Gaubin M., Robert-Hebmann V., Zhang X., Murali R., Greene M. I., Piatier-Tonneau D. and Devaux C. (1997) Transduction of activation signal that follows HIV-1 binding to CD4 and CD4 dimerization involve the immunoglobulin CDR-3-like region in domain 1 of CD4. J. Biol. Chem. 272, 19441-19450.
• Signoret N., de Jonc J., Goudsmit J., and Sattentau Q. J. (1997) Mutations within the CD4-CDR-3-like loop allow replication in an immortalised T cell line of HIV-1 viruses chimeric for envelope glycoproteins containing non-syncytium-inducing V3 loop. AIDS Res. Hum. Retroviruses 13, 121-123.
• Signoret N., Blanc-Zouaoui D., Kwong P., and Sattentau Q. J. (1996) Selective effects of electrostatic changes in the CD4 CDR-3-like loop on infection by different Human Immunodeficiency virus type 1 isolates. AIDS Res. Hum. Retroviruses 12, 1001-1013.
• Hill A., Steven P., Haurun J., Murray N., Yao Q., Rowe M., Signoret N., Rickinson A., and McMichael A. (1995) Class I Major Histocompatibility Complex-restricted cytotoxic lymphocytes specific for Ebstein-Barr virus (EBV) nuclear antigen fail to lyse the EBV-transformed B lymphoblastoid cell lines against which they were raised. J. Exp. Med. 181, 2221.
• Zelphati O., Imbach J. L., Signoret N., Zong G., Rayner B. and Lezerman L. (1994) Antisens oligonucleotides in solution or encapsulated in immunoliposomes inhibit replication of HIV-1 by several different mechanisms. Nucleic Acids Res. 22, 4307.
• Lazaro I., Naniche D., Signoret N., Bernard A-M., Marguet D., Klatzmann D., Drajic T., Alizon M., and Sattentau Q. J. (1994) Factors involved in entry of the human immunodeficiency virus type 1 into permissive cells: lack of evidence for a role of CD26. J. Virol. 68, 6535.
• Signoret N., Poignard P., Blanc D., and Sattentau Q. J. (1993) Human and Simian Immunodeficiency viruses: virus-receptor interaction. Trends in Microbiology 1, 328.

Teaching

Undergraduate

• Immunology
  Biology year two (practicals)
• Advanced topics in immunology
  Biology year three (three lectures)
• Biomedicine module
  Biology year two (two lectures)
• Intracellular signalling
  HYMS year one, block one, lecture
• Information skill
  HYMS year one, term one, student selective course
  

External activities

Memberships

• British Society for Cell Biology (BSCB)
  Member

Editorial duties

• PloS ONE
  Academic Editor (2011 - )