Human CD4+ T cell subsets differ in their abilities to cross endothelial and epithelial brain barriers in vitro

Abstract

Background: The brain barriers establish compartments in the central nervous system (CNS) that significantly differ in their communication with the peripheral immune system. In this function they strictly control T-cell entry into the CNS. T cells can reach the CNS by either crossing the endothelial blood-brain barrier (BBB) or the epithelial bloodcerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP). Objective: Analysis of the cellular and molecular mechanisms involved in the migration of different human CD4 + T-cell subsets across the BBB versus the BCSFB. Methods: Human in vitro models of the BBB and BCSFB were employed to study the migration of circulating and CNS-entry experienced CD4 + T helper cell subsets (Th1, Th1*, Th2, Th17) across the BBB and BCSFB under inflammatory and non-inflammatory conditions in vitro. Results: While under non-inflammatory conditions Th1* and Th1 cells preferentially crossed the BBB, under inflammatory conditions the migration rate of all Th subsets across the BBB was comparable. The migration of all Th subsets across the BCSFB from the same donor was 10-to 20-fold lower when compared to their migration across the BBB. Interestingly, Th17 cells preferentially crossed the BCSFB under both, non-inflamed and inflamed conditions. Barriercrossing experienced Th cells sorted from CSF of MS patients showed migratory characteristics indistinguishable from those of circulating Th cells of healthy donors. All Th cell subsets could additionally cross the BCSFB from the CSF to ChP stroma side. T-cell migration across the BCSFB involved epithelial ICAM-1 irrespective of the direction of migration. Conclusions: Our observations underscore that different Th subsets may use different anatomical routes to enter the CNS during immune surveillance versus neuroinflammation with the BCSFB establishing a tighter barrier for T-cell entry into the CNS compared to the BBB. In addition, CNS-entry experienced Th cell subsets isolated from the CSF of MS patients do not show an increased ability to cross the brain barriers when compared to circulating Th cell subsets from healthy donors underscoring the active role of the brain barriers in controlling T-cell entry into the CNS. Also we identify ICAM-1 to mediate T cell migration across the BCSFB.

Exploring the Use of Dimethyl Fumarate as Microglia Modulator for Neurodegenerative Diseases Treatment

“…It is considered a prototypic organ-specific autoimmune disease, targeting the CNS with inflammatory lesions, demyelination, axonal/neuronal damage, and metabolic changes [6,7]. In particular, many studies on the immune system of MS patients indicated that T and B cells, and probably also autoantibodies are key factors contributing to its immunopathogenesis [6,[8][9][10]. Indeed, autoreactive CD4+ T cells with Th1 (secreting IFN-γ) or Th1* (secreting IFN-γ and IL-17), or those secreting IFN-γ and GM-CSF [6,11,12], play an important role in MS. On this regard, DMF immunomodulatory effects for MS treatment are achieved by the Th1 to Th2 shift and by the modulation of the dendritic cells' function [13].…”

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

“…After 6 days of co-culture, the resulting hBLECs express TJ proteins at cell-cell contacts and transporters typically observed in the brain endothelium, maintaining the properties of in vivo BBB for at least 20 days [28], a period during which we performed transport experiments. This model is now widely used to investigate BBB physiology, as well as molecules and cells passage across the BBB [80][81][82][83][84][85]. The loading of the human BBB model with GM1 or OligoGM1, followed by the measure of permeability parameters, provided evidence to consider OligoGM1 as a molecule transported by the paracellular mechanism, and importantly with a rate 20-fold higher then ganglioside GM1 (Figure 3).…”

In vitro modeling of blood–brain barrier and interface functions in neuroimmune communication

“…One area of development in Axis 4 is the evaluation of immune cell trafficking across other brain interfaces, such as across choroid plexus epithelial cells. In vitro models have evaluated primary vs. cell lines of choroid plexus epithelial cells [105] and found that the trafficking of human T-cell subsets differed in human BECs vs. a choroid plexus epithelial cell line under baseline and inflammatory conditions [106]. Given the importance of these barriers in immune surveillance, responses to injury, and other CNS functions [1], development of novel in vitro models to study them could be an important approach to advance the field.…”