Anne Astier's lab studies the regulation of human T cell activation in health and disease.
Controlled T cell immunity is a prerequisite for health. Any wrongdoing and the individual will for example develop autoimmune diseases if the immune system reacts too strongly, or allow tumour expansion due to inadequate immune response. Hence, the control mechanisms for accurate T cell activation and T cell differentiation are essential to maintain a good immune homeostasis. The complete understanding of the factors controlling immunity is likely to help to understand human pathologies.
Multiple sclerosis (MS) is a chronic inflammatory disease, with inflammation in the brain. It is a complex disease that involves multiple aspects (immunologic, genetics and environmental), and although several mechanisms have been uncovered, the understanding of MS pathogenesis is far from complete. CD46 controls the acquired immune response. It is a complement regulatory molecule that protects the cells from autolysis. On top of its role in innate immunity, CD46 also controls T cell fate. Its activation leads to T cell activation, Tr1 differentiation and IL-10 production, and it appears to control inflammation. We previously demonstrated that the CD46 pathway was altered in patients with MS. Upon CD46 activation, both T cells and dendritic cells exhibit a pro-inflammatory phenotype, compared to cells from healthy donors. Similar defects have now been identified in other inflammatory diseases suggesting that CD46 is key in controlling T cell homeostasis.
We investigate the molecular mechanisms involved in the regulation of human T cell activation. As a faculty CNRS scientist in France, this major research interest started when I designed a project to determine the role of the complement receptor CD46 in the adaptive immune response. We were the first to describe the role of CD46 in the control of T cell responses (Astier JI 2000, Zaffran JI, 2001, Marie Nat Immunol 2002). Back to Harvard, with David Hafler, we demonstrated that the CD46 pathway was defective in T cells from patients with autoimmune diseases (multiple sclerosis – MS, Astier, JCI, 2006). Now in Edinburgh, we focus on determining the molecular mechanisms involved in the regulation of human T cell activation and on analyzing these in MS and other chronic inflammatory diseases. This may provide useful novel drug targets for these diseases.
During these past years, we have focused on the regulation of CD46 expression on T cells. We have notably shown that CD46 was processed upon T cell activation. Its ectodomain is cleaved by matrix metalloproteinases upon CD46 coactivation, and its cytoplasmic tails are cleaved by the gamma-secretase (Ni Choileain 2011, 2012). This provides an on/off signal for the T cells. Indeed, CD46 expression at the surface of T cells is tightly controlled: CD46 activation, several mediators such as PGE2 and vitamin D, and interaction with other cells, all of these affect CD46 expression and T cell responses (Kickler 2012a, Kickler 2012b, Charron in press 2015). This tight regulation of expression led us to collaborate with Andre Lieber and Darrick Carter (Seattle) who made recombinant proteins allowing to target CD46 on human cells and, again, these proteins strongly modulate T cell activation (Hay 2014). We are now further investigating the molecular pathways involved in controlling CD46 expression in activated T cells, and how this impacts overall on T cell activation. In parallel, we explore these pathways in patient cells in order to pinpoint the mechanisms responsible for the impaired control of inflammation observed in T cells from patients with MS or other chronic inflammatory diseases.
After graduating from the University of Pierre et Marie Curie (Paris VI), I performed a postdoctoral fellowship at the Dana-Farber Cancer Institute, Harvard Medical School, in the laboratory of Professor Arnold Freedman on integrin functions in human B cells. In 1998, I obtained an academic tenure faculty position at the "National Center for Scientific Research" (CNRS) in France where I developed the project on the role of CD46 in T cell activation at the INSERM Unit directed by Chantal Rabourdin-Combe. I took a leave of absence from CNRS in 2001 to return to the States. I worked on integrins for 2 more years before going back to T cells and CD46 in the context of autoimmunity with Professor David Hafler, where I became a faculty member at Harvard Medical School as an instructor in Neurology in 2004. I joined the University of Edinburgh in 2007 and received a grant from the MS society.
Many students have rotated in the lab, the first one, Alice Pannerec, summer internship for Agro Rennes diploma, summer 2007, went on for her PhD in Paris;
Several exchange students from around the world: Christian Neumann, Diploma thesis (Sept 2008-March 2009), then PhD student in Berlin; Melissa Ruck, from Rochester Uni (2009), then PhD student at UCSF; Tess Petersen from Rochester Uni (2011) now at the NIH; Karoline Kickler, BSc from Germany (Oct-March 2011) then MSc student in Germany; Laurien Rook, from the Netherlands; Joanna Szymczak from Poland (2011);
Several UoE Immunology honours students: Amy Sawtell (2008); Dana Photiou (2009); Kathryn Maltby (2010); Katherine Mathieson (2011), Barbora Tuharska and Ellen MacFarlane (2014).
MSc students: Dongqing Ma (2012), Prasun Dutta, MSc student in bioinformatics (distinction 2011); Lauren Charron, MSc in biomedical sciences, Edinburgh; Axelle Doctrinal, M2 Lille; Hoa-Yu Yang, MSc Edinburgh; Joanne Hay, MSc inflammation Edinburgh (top of her class, distinction 2013), Nivedya Swarnalekha, MSc Biotechnology (with distinction 2014), Mario Armando Gómez Salazar, MSc Biotechnology (with distinction 2014), Lisa Kelly, MSc Inflammation (with distinction 2015), Daniel Camargo-Latorre, MSc Biotechnology (2015)
Some summer students: Chungbin Yoo, Darrah Craughwell, Ahmed Bourhane, Mathilde Mercat, Sarah Inglesfield, Patrick McCallum, Santi Trainor Moss.
And Jillian Stephen, volunteer post-doctoral research assistant!
Our great Siobhan Ni Choileain (PhD student) is now doing her postdoc at Yale.
Thanks to all for coming!