T-Lymphocytes Traffic into the Brain across the Blood-CSF Barrier: Evidence Using a Reconstituted Choroid Plexus Epithelium

Abstract

An emerging concept of normal brain immune surveillance proposes that recently and moderately activated central memory T lymphocytes enter the central nervous system (CNS) directly into the cerebrospinal fluid (CSF) via the choroid plexus. Within the CSF space, T cells inspect the CNS environment for cognate antigens. This gate of entry into the CNS could also prevail at the initial stage of neuroinflammatory processes. To actually demonstrate T cell migration across the choroidal epithelium forming the blood-CSF barrier, an in vitro model of the rat blood-CSF barrier was established in an “inverse” configuration that enables cell transmigration studies in the basolateral to apical, i.e. blood/stroma to CSF direction. Structural barrier features were evaluated by immunocytochemical analysis of tight junction proteins, functional barrier properties were assessed by measuring the monolayer permeability to sucrose and the active efflux transport of organic anions. The migratory behaviour of activated T cells across the choroidal epithelium was analysed in the presence and absence of chemokines. The migration pathway was examined by confocal microscopy. The inverse rat BCSFB model reproduces the continuous distribution of tight junction proteins at cell margins, the restricted paracellular permeability, and polarized active transport mechanisms, which all contribute to the barrier phenotype in vivo. Using this model, we present experimental evidence of T cell migration across the choroidal epithelium. Cell migration appears to occur via a paracellular route without disrupting the restrictive barrier properties of the epithelial interface. Apical chemokine addition strongly stimulates T cell migration across the choroidal epithelium. The present data provide evidence for the controlled migration of T cells across the blood-CSF barrier into brain. They further indicate that this recruitment route is sensitive to CSF-borne chemokines, extending the relevance of this migration pathway to neuroinflammatory and neuroinfectious disorders which are typified by elevated chemokine levels in CSF.

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Another study found only a marginal increase in T cells in the stroma [129], that can be interpreted as the choroid plexuses being gateway to the CSF during EAE rather than sites of accumulation per se. On the other hand in vitro studies employing inverse configurations of the BCSFB have provided solid evidence for the migration of activated T cells from the basolateral to apical site of choroid plexus epithelial cells in response to CSF derived factors such as CXCL12 [77,147]. These observations raise the question if there is an alternative route for T-cell entry into the CNS from the choroid plexus stroma.…”

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

“…They are not the only immune cell in the brain. Other immune cell types include, but are not limited to, macrophages and lymphocytes (Strazielle et al 2016). Perivascular, meningeal, and choroid plexus macrophages also reside at the CNS interface (Goldmann et al 2016).…”

Primary effusion lymphoma involving cerebrospinal fluid, deep cervical lymph nodes and adenoids. Report of a case supporting the lymphatic connection between brain and lymph nodes

“…SELPLG and CORO1C ) and their immunohistochemically strongly expressed protein products (selectin‐P ligand and coronin‐1C) have been given a pathogenetic role, given the role of these proteins in cell migration‐chemotaxis and cell motility, respectively. P‐selectin is expressed selectively by choroid plexus and meningeal vessels, and the expression of its ligand could explain access of neoplastic cells from the circulation into the CSF, as has been proven for T‐lymphocytes during normal brain immune surveillance . Involvement of CSF in some of the previously reported cases in which cerebral masses were present can be attributed simply to direct extension from involved superficial brain parenchyma.…”

“…Pselectin is expressed selectively by choroid plexus and meningeal vessels, and the expression of its ligand could explain access of neoplastic cells from the circulation into the CSF, as has been proven for T-lymphocytes during normal brain immune surveillance. 43 Involvement of CSF in some of the previously reported cases in which cerebral masses were present 3,4 can be attributed simply to direct extension from involved superficial brain parenchyma. The lymph node involvement in our case lends support to the recently described finding (mostly in animal models, but also in humans) of a lymphatic connection between CSF and deep cervical lymph nodes.…”