blood-cerebrospinal fluid barrier; adhesion molecules; CNS immunosurveillance; live cell imaging; experimental autoimmune encephalomyelitis; blood-brain barrier; T cell subsets (Th1, Th17, Tc1, Tc17); T cell trafficking
Hamminger Patricia, Marchetti Luca, Preglej Teresa, Platzer René, Zhu Ci, Kamnev Anton, Rica Ramona, Stolz Valentina, Sandner Lisa, Alteneder Marlis, Kaba Elisa, Waltenberger Darina, Huppa Johannes B., Trauner Michael, Bock Christoph, Lyck Ruth, Bauer Jan, Dupré Loïc, Seiser Christian, Boucheron Nicole, Engelhardt Britta, Ellmeier Wilfried (2021), Histone deacetylase 1 controls CD4+ T cell trafficking in autoinflammatory diseases, in Journal of Autoimmunity
, 119, 102610-102610.
Haghayegh Jahromi Neda, Marchetti Luca, Moalli Federica, Duc Donovan, Basso Camilla, Tardent Heidi, Kaba Elisa, Deutsch Urban, Pot Caroline, Sallusto Federica, Stein Jens V., Engelhardt Britta (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, in Frontiers in Immunology
, 10, 1.
(2019), Pharmacological Inhibition of Acid Sphingomyelinase Ameliorates Experimental Autoimmune Encephalomyelitis, in Neurosignals
, 27(S1), 20-31.
Wimmer Isabella, Tietz Silvia, Nishihara Hideaki, Deutsch Urban, Sallusto Federica, Gosselet Fabien, Lyck Ruth, Muller William A., Lassmann Hans, Engelhardt Britta (2019), PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation, in Frontiers in Immunology
, 10, 711.
Tietz Silvia, Périnat Therese, Greene Gretchen, Enzmann Gaby, Deutsch Urban, Adams Ralf, Imhof Beat, Aurrand-Lions Michel, Engelhardt Britta (2018), Lack of junctional adhesion molecule (JAM)-B ameliorates experimental autoimmune encephalomyelitis, in Brain, Behavior, and Immunity
, 73, 3-20.
Engelhardt Britta, Vajkoczy Peter, Weller Roy O (2017), The movers and shapers in immune privilege of the CNS, in Nature Immunology
, 18(2), 123-131.
The endothelial blood-brain barrier (BBB) in central nervous system (CNS) microvessels and the epithelial blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus establish the interface between the immune system and the CNS. Several aspects of their function to maintain CNS homeostasis contribute to rigorous control of immune cell trafficking into the CNS. Passage into the CNS is therefore limited to immune cell subsets that hold molecular keys required to breach these barriers. During homeostatic CNS immunosurveillance specific T cell subsets breach the brain barriers but remain confined to the cerebrospinal fluid (CSF) filled ventricular and leptomeningeal spaces. In contrast, in multiple sclerosis (MS) or in its animal model, experimental autoimmune encephalomyelitis (EAE), barrier properties of the BBB and BCSFB change and allow the migration of pathogenic T cells into the CNS. Therapeutic targeting of T cell migration into the CNS has proven beneficial for the treatment of MS but in rare cases it is associated with severe side effects like progressive multifocal leukoencephalopathy (PML). This has raised significant concerns about the safety of therapies targeting T cell trafficking as these might also affect the migration of beneficial T cell subsets maintaining immunosurveillance of the CNS. However, the anatomical routes and molecular mechanisms involved in T cell migration into the CNS during immunosurveillance and how these mechanisms differ in brain and psinal cord and change during neuroinflammation are not sufficiently explored. Our previous research has significantly contributed to the notion that different T cell subsets like effector CD4+ Th1 versus Th17 cells or CD8+ T cells use different anatomical routes and different molecular mechanisms to breach the brain barriers during onset and progression of CNS neuroinflammation. Furthermore, we have shown an active contribution of the BBB which depending on its inflammatory status directs T cells to paracellular or transcellular sites of diapedesis. The proposed research project aims to uncover the anatomical routes and molecular cues used by different CD4 and CD8 effector T cell subsets for breaching the BBB or the BCSFB during immunosurveillance and neuroinflammation. To address this challenging task we have combined a unique armamentarium of in vivo models of Th1, Th17 and CD8 T cell mediated autoimmune CNS inflammation combined with in vitro models of the BBB and the BCSFB and in vitro and in vivo live cell imaging technology to study T cell interaction with the brain barriers. Under Specific Aim 1 we will dissect the role of cell adhesion molecules from the Ig superfamily (IgCAMs) in Th1 versus Th17 migration across the brain barriers during immunosurveillance and EAE and the role for paracellular versus transcellular diapedesis pathways of T cells across the BBB and the mechanisms involved. Specific Aim 2 is dedicated to explore the molecular mechanism involved in CD8 T cell migration into the CNS during immunosurveillance and neuroinflammation employing a mouse model of CD8 T cell mediated autoimmune CNS inflammation. Finally, to explore the relevance of the BBB versus the BCSFB as T cell entry port into the CNS we will investigate under Specific Aim 3 the role of the choroid plexus as alternative entry site of T cells into the CSF space during immunosurveillance and neuroinflammation. Exploring these research goals in parallel is prerequisite for obtaining the unique opportunity for direct cross-fertilization of the respective projects and thus increasing awareness for differences observed for the different T cell subsets in crossing the brain barriers. Our research will serve to significantly improve our understanding of the anatomical routes and molecular mechanisms guiding different T cell subsets into the CNS during immunosurveillance and neuroinflammation. In general, this will set the stage to more accurately foresee CNS specific adverse effects of the increasing numbers of therapies targeting T cell trafficking or even depleting T cells in many chronic inflammatory diseases. Additionally, this will allow to identify novel therapeutic targets at the level of the brain barriers suited to specifically block CNS recruitment of destructive T cells, while leaving the migration of protective T cell subsets into the CNS unaffected.