ESR 8 vision / project

ESR 8: December 10, 2019; PhD Immunology

Brain endothelial mechanisms directing the cellular pathway of T cell migration across the BBB

Project Results

Luca Marchetti made use of primary mouse brain microvascular endothelial cells (pMBMECs) as in vitro model of the BBB to study the molecular mechanisms directing paracellular versus transcellular T cell diapedesis across the blood-brain barrier (BBB) under physiological flow in vitro. In multiple sclerosis autoaggressive T helper (Th) 1 and Th17 cells cross the BBB to reach the central nervous system (CNS), where they induce neuroinflammation. We found that both, Th1 and Th17 cells require endothelial ICAM-1 and ICAM-2 for crawling on the BBB to find sites permissive for diapedesis. Nevertheless, lack of ICAM-1 and ICAM-2 affected Th17 entry into the brain to a larger degree than their migration into the spinal cord, suggesting presence of different trafficking cues at the BBB in the spine versus the brain. (Haghayegh Jahromi, Marchetti et al., Front Immunol, 2019, in press).

Using the pMBMECs as in vitro model of the BBB Luca also compared in collaboration with David Francisco (ESR4) the transcriptome profile of pMBMECs favoring transcellular over paracellular T-cell diapedesis by RNA sequencing (RNA-seq). We identified 8 candidate genes specifically upregulated in pMBMECs favoring transcellular T-cell diapedesis. Protein expression of the candidate genes at the inflamed BBB in vitro and in vivo has been confirmed. Making use of pMBMECs lacking one of the candidate genes preliminary observations confirm contribution of this molecule in directing T cells to transcellular sites of diapedesis. These observations will be submitted for publication in March 2020.

Awards

3rd Poster Prize Gordon Research Seminar Barriers of the CNS, June 2018, Colby Sawyer College, NH, USA

Selected Poster Talk a the 22nd International Symposium on Signal Transduction at the Blood-Brain Barriers”, September 2019, Würzburg, Germany

Title of PhD thesis

Brain endothelial mechanisms directing the cellular pathway of T cell migration across the BBB

Current position

Scientific Engagement Coordinator at Biogen

BtRAIN publications

Luca Marchetti, David Francisco, Isabelle Gruber, Sasha Soldati, Aude Thiriot, Ulrich von Andrian, Urban Deutsch, Ruth Lyck, Rémy Bruggmann, Britta Engelhardt. 2021. ACKR1 favors transcellular over paracellular T-cell diapedesis across the blood-brain barrier in neuroinflammation in vitro. Eur J Immunol. Online ahead of print. https://doi.org/10.1002/eji.202149238

Patricia Hamminger, Luca Marchetti, Teresa Preglej, Rene Platzer, Ci Zhu, Anton Kamnev, Ramona Rica, Valentina Stolz, Lisa Sandner, Marlis Alteneder, Elisa Kaba, Darina Waltenberger, Johannes Huppa, Michael Trauner, Christoph Bock, Ruth Lyck, Jan Bauer, Loïc Dupré, Nicole Boucheron, Britta Engelhardt, Wilfried Ellmeier. 2021. Histone deacetylase 1 controls CD4+ T cell trafficking in autoinflammatory diseases. J Autoimmunity Feb 20;119: 102610. https://doi.org/10.1016/j.jaut.2021.102610

David M. F. Francisco, Luca Marchetti, Sabela Rodríguez-Lorenzo, Eduardo Frias, Ricardo M. Figueiredo, BtRAIN Network, Peter Winter, Ignacio Andres Romero, Helga E. de Vries, Britta Engelhardt*, Rémy Bruggmann. 2020. Advancing brain barriers RNA sequencing: guidelines from experimental design to publication. FBCNS 17, Article number: 51. https://doi.org/10.1186/s12987-020-00207-2

Haghayegh Jahromi N, Luca Marchetti, Federica Moalli, Donovan Duc, Camilla Basso, Heidi Tardent, Elisa Kaba, Urban Deutsch, Caroline Pot, Federica Sallusto, Jens V. Stein, Britta Engelhardt. 2020. Intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 differentially contribute to peripheral activation and CNS entry of autoaggressive Th1 and Th17 cells in experimental autoimmune encephalomyelitis. Front. Immunol. 10:3056. eCollection 2019. https://doi.org/10.3389/fimmu.2019.03056

Marchetti L and B Engelhardt. 2020. Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation. Vasc Biol –March 20, https://doi.org/10.1530/VB-19-0033