thierry walzer
  • E-mail :[email]
  • Phone : +33 4 37 28 23 73
  • Location : Lyon, France
Last update 2013-04-18 10:39:19.94

thierry walzer PhD Immunology

Course and current status

During my scientific career, I have studied the immune response under different angles and in academic and industrial environments. Throughout my experiences, I’ve always been interested in cellular differentiation and migration, and how these two phenomena are linked in the immune system. During my PhD, I studied CD8 T cell memory in mice. Using differential display analyses, I found that resting memory CD8 T cells expressed high levels of CCL5 mRNA. As a result, they have the unique capacity compared to naive T cells to rapidly secrete CCL5 upon ex vivo antigenic stimulation. CCL5 secretion is mainly due to the translation of the pre-existing mRNA. This original mode of “memorization” could also be used for other genes as suggested by our unpublished analyses. During my postdoc in Amgen Inc., I studied the role of semaphorins and plexins in the immune system. Semaphorins are best known for their repulsive activity on axon guidance in neurons. Emerging evidence also shows that these proteins are expressed in the immune system where their role is largely unknown. A semaphorin homolog called A39R is expressed by several poxviruses like Vaccinia and binds to Plexin C1. I showed that Plexin C1 is expressed by dendritic cells (DCs) and that A39R inhibited integrin-mediated adhesion and DC spreading in vitro in a similar manner to what was described for neurons. Furthermore, A39R inhibited chemokine-induced migration of DCs in vitro and phagocytosis of bacteria or apoptotic bodies by DCs in vivo. This data suggests that viruses use semaphorin homologs to evade the host immune system. For my second postdoc, in Eric Vivier’s lab in Marseille, I used a microarray-based strategy to identify transcripts that were specifically expressed in mouse and human NK cells compared to all other types of leukocytes. The aim was both to identify a cell surface marker of mammalian NK cells and to identify novel molecular pathways regulating NK cell functions. I made two important discoveries: first, the expression of the activating receptor NKp46 is restricted to mammalian NK cells. Thus, NK cells can be identified in situ or by flow cytometry using anti-NKp46 antibodies. I then went on to generated a mouse transgenic model of transient ablation of NK cells by taking advantage of NKp46 regulatory regions and the diphtheria toxin receptor system. Second, I found that mammalian NK cells specifically express S1P5, a G-coupled receptor to sphingosine-1 phosphate. I found that S1P5 is a chemotactic receptor, promoting NK cell egress from their sites of development, the bone marrow, into the blood where the local concentration of sphingosine-1 phosphate is high. This study was the first hint on the mechanisms of NK cell trafficking at steady-state. Our current research aims to understand how S1P5 coordinates with chemokine receptors to guide cytotoxic lymphocytes. Moreover, we study the function of several other genes that we found to be NK-specific using genetic approaches.During my scientific career, I have studied the immune response under different angles and in academic and industrial environments. Throughout my experiences, I’ve always been interested in cellular differentiation and migration, and how these two phenomena are linked in the immune system. During my PhD, I studied CD8 T cell memory in mice. Using differential display analyses, I found that resting memory CD8 T cells expressed high levels of CCL5 mRNA. As a result, they have the unique capacity compared to naive T cells to rapidly secrete CCL5 upon ex vivo antigenic stimulation. CCL5 secretion is mainly due to the translation of the pre-existing mRNA. This original mode of “memorization” could also be used for other genes as suggested by our unpublished analyses. During my postdoc in Amgen Inc., I studied the role of semaphorins and plexins in the immune system. Semaphorins are best known for their repulsive activity on axon guidance in neurons. Emerging evidence also shows that these proteins are expressed in the immune system where their role is largely unknown. A semaphorin homolog called A39R is expressed by several poxviruses like Vaccinia and binds to Plexin C1. I showed that Plexin C1 is expressed by dendritic cells (DCs) and that A39R inhibited integrin-mediated adhesion and DC spreading in vitro in a similar manner to what was described for neurons. Furthermore, A39R inhibited chemokine-induced migration of DCs in vitro and phagocytosis of bacteria or apoptotic bodies by DCs in vivo. This data suggests that viruses use semaphorin homologs to evade the host immune system. For my second postdoc, in Eric Vivier’s lab in Marseille, I used a microarray-based strategy to identify transcripts that were specifically expressed in mouse and human NK cells compared to all other types of leukocytes. The aim was both to identify a cell surface marker of mammalian NK cells and to identify novel molecular pathways regulating NK cell functions. I made two important discoveries: first, the expression of the activating receptor NKp46 is restricted to mammalian NK cells. Thus, NK cells can be identified in situ or by flow cytometry using anti-NKp46 antibodies. I then went on to generated a mouse transgenic model of transient ablation of NK cells by taking advantage of NKp46 regulatory regions and the diphtheria toxin receptor system. Second, I found that mammalian NK cells specifically express S1P5, a G-coupled receptor to sphingosine-1 phosphate. I found that S1P5 is a chemotactic receptor, promoting NK cell egress from their sites of development, the bone marrow, into the blood where the local concentration of sphingosine-1 phosphate is high. This study was the first hint on the mechanisms of NK cell trafficking at steady-state. Our current research aims to understand how S1P5 coordinates with chemokine receptors to guide cytotoxic lymphocytes. Moreover, we study the function of several other genes that we found to be NK-specific using genetic approaches.jililzrghrhtzetrgg

Scientific summary

In my previous lab, I used a microarray-based strategy to identify transcripts that were specifically expressed in mouse and human NK cells compared to all other types of leukocytes. The aim was both to identify a cell surface marker of mammalian NK cells and to identify novel molecular pathways regulating NK cell functions. I made two important discoveries: first, the expression of the activating receptor NKp46 is restricted to mammalian NK cells. Thus, NK cells can be identified in situ or by flow cytometry using anti-NKp46 antibodies. I then went on to generated a mouse transgenic model of transient ablation of NK cells by taking advantage of NKp46 regulatory regions and the diphtheria toxin receptor system. Second, I found that mammalian NK cells specifically express S1P5, a G-coupled receptor to sphingosine-1 phosphate. I found that S1P5 is a chemotactic receptor, promoting NK cell egress from their sites of development, the bone marrow, into the blood where the local concentration of sphingosine-1 phosphate is high. This study was the first hint on the mechanisms of NK cell trafficking at steady-state. In 2009, I moved to Lyon to start the lab of "immunity and cytotoxic lymphocytes".  We are interested in the molecular events that regulate the differentiation of cytotoxic lymphocytes and we use NK cells as cellular models. Our current research axis are i) the study of the role of several transcription factors that we selected on the basis of their expression pattern in the immune system. ii) the study of the role of several novel tyrosine kinases in NK cell differentiation. iii) the study of the coordination between S1P and chemokine receptors during NK cell trafficking in vivo. Our strategy is based on the use of genetically modified mouse strains and we also try to validate our findings in human, thanks to a collaboration with local hospitals and clinicians.

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