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

Nishihara, Hideaki; Soldati, Sasha; Mossu, Adrien; Rosito, Maria; Rudolph, Henriette; Muller, William A; Latorre, Daniela; Sallusto, Federica; Sospedra, Mireia; Martin, Roland; Ishikawa, Hiroshi; Tenenbaum, Tobias; Schroten, Horst; Gosselet, Fabien; Engelhardt, Britta (2020). Human CD4+ T cell subsets differ in their abilities to cross endothelial and epithelial brain barriers in vitro. Fluids and barriers of the CNS, 17(1), p. 3. BioMed Central 10.1186/s12987-019-0165-2

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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 blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP).


Analysis of the cellular and molecular mechanisms involved in the migration of different human CD4+ T-cell subsets across the BBB versus the BCSFB.


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.


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. Barrier-crossing 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.


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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

Graduate School:

Graduate School Gender Studies

UniBE Contributor:

Nishihara, Hideaki; Soldati, Sasha Giulio Natale; Mossu, Adrien; Rosito, Maria and Engelhardt, Britta


500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health




BioMed Central




Ursula Zingg-Zünd

Date Deposited:

21 Jan 2021 09:00

Last Modified:

13 Mar 2021 14:58

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Adhesion molecule Blood-cerebrospinal fluid barrier Blood–brain barrier Multiple sclerosis T-cell migration




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