Journal Article

Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid

Mielke, Dorothee, Issekutz, Thomas, Brylla, Elke, Flügel, Alexander, Bechmann, Ingo, Schläger, Christian, Lodygin, Dmitri, Rohde, Veit, Krueger, Martin, Odoardi, Francesca, Vidoli, Stefano, Körner, Henrike, Haberl, Michael, Nelson, Peter J., Ziemssen, Tjalf, Cabañas, Carlos

2016

Overview

By investigating trafficking of autoreactive T cells into the CSF during experimental autoimmune encephalitis, the authors find that T cells enter the CSF from the leptomeninges, and that commuting between the leptomeninges and the CSF is regulated by integrin adhesive forces triggered by T-cell activation and/or chemokines. T cell exchange between blood and brain Alexander Flügel and colleagues investigate the mechanisms by which inflammation-inducing autoreactive T cells are trafficked from peripheral blood to the brain during adoptive transfer in experimental autoimmune encephalomyelitis (EAE) in rats, a model of multiple sclerosis. They show that T cells enter the cerebrospinal fluid (CSF) from the leptomeningeal space rather than the choroid plexus, which has been suggested as a source. The trafficked T cells maintained their full antigen responsiveness and pathogenic potential, suggesting that the characterization of readily accessible T cells in the CSF could be relevant to the properties and function of pathogenic T cells in multiple sclerosis. In multiple sclerosis, brain-reactive T cells invade the central nervous system (CNS) and induce a self-destructive inflammatory process. T-cell infiltrates are not only found within the parenchyma and the meninges, but also in the cerebrospinal fluid (CSF) that bathes the entire CNS tissue 1 , 2 . How the T cells reach the CSF, their functionality, and whether they traffic between the CSF and other CNS compartments remains hypothetical 3 , 4 , 5 , 6 . Here we show that effector T cells enter the CSF from the leptomeninges during Lewis rat experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. While moving through the three-dimensional leptomeningeal network of collagen fibres in a random Brownian walk, T cells were flushed from the surface by the flow of the CSF. The detached cells displayed significantly lower activation levels compared to T cells from the leptomeninges and CNS parenchyma. However, they did not represent a specialized non-pathogenic cellular sub-fraction, as their gene expression profile strongly resembled that of tissue-derived T cells and they fully retained their encephalitogenic potential. T-cell detachment from the leptomeninges was counteracted by integrins VLA-4 and LFA-1 binding to their respective ligands produced by resident macrophages. Chemokine signalling via CCR5/CXCR3 and antigenic stimulation of T cells in contact with the leptomeningeal macrophages enforced their adhesiveness. T cells floating in the CSF were able to reattach to the leptomeninges through steps reminiscent of vascular adhesion in CNS blood vessels, and invade the parenchyma. The molecular/cellular conditions for T-cell reattachment were the same as the requirements for detachment from the leptomeningeal milieu. Our data indicate that the leptomeninges represent a checkpoint at which activated T cells are licensed to enter the CNS parenchyma and non-activated T cells are preferentially released into the CSF, from where they can reach areas of antigen availability and tissue damage.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/371 / 631/250/38 / Adoptive Transfer / Animals / Antigens / Autoimmune diseases / Body fluids / Care and treatment / Cell Adhesion / Cell Movement / Central nervous system / Cerebrospinal fluid / Cerebrospinal Fluid - cytology / Cerebrospinal Fluid - immunology / Chemokines / Chemokines - metabolism / Choroid Plexus / Collagen - metabolism / Complications and side effects / Cytokines / Disease Models, Animal / Encephalomyelitis, Autoimmune, Experimental - immunology / Encephalomyelitis, Autoimmune, Experimental - pathology / Female / Gene expression / Humanities and Social Sciences / Inflammation / Influence / Integrin alpha4beta1 - metabolism / letter / Lymphocyte Activation / Lymphocyte Function-Associated Antigen-1 - metabolism / Lymphocytes / Macrophages - immunology / Macrophages - metabolism / Male / Meninges - immunology / Meninges - pathology / Meningitis / Microscopy / multidisciplinary / Multiple Sclerosis - immunology / Multiple Sclerosis - pathology / Rats / Rats, Inbred Lew / Receptors, CCR5 - metabolism / Receptors, CXCR3 - metabolism / Science / Spinal cord / T cell receptors / T cells / T-Lymphocytes - immunology / T-Lymphocytes - pathology