Acquisition of residency programs by T cells entering the human brain

TY - JOUR

T1 - Acquisition of residency programs by T cells entering the human brain

AU - Hsiao, Cheng-Chih

AU - Engelenburg, Hendrik J

AU - Rip, Jasper

AU - Wierenga-Wolf, Annet F

AU - van Puijfelik, Fabiënne

AU - van Luijn, Marvin M

AU - Huitinga, Inge

AU - Hamann, Jörg

AU - Smolders, Joost

N1 - Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2025/7/9

Y1 - 2025/7/9

N2 - T cell surveillance is mandatory for maintaining central nervous system (CNS) homeostasis, while aberrant accumulation is linked to neuroinflammation. To explore the residency programs acquired by T cells through different anatomical locations of the human brain, we isolated CD8+ and CD4+ T cells from CNS border compartments (choroid plexus and leptomeninges), intrathecal compartments (cerebrospinal fluid [CSF] and subcortical white matter [WM]), and paired peripheral blood of brain donors. Flow cytometry revealed a shared effector memory phenotype across CNS compartments that was partially induced in circulating T cells interacting with brain endothelium in vitro. Intrathecal T cells expressed full tissue-residency traits, yet T cells from WM, compared to CSF, showed reduced expression of migratory, co-stimulatory, and recent activation markers despite a similar cytokine response upon ex vivo activation. This work demonstrates the versatility of T cell phenotypes across CNS compartments and provides insight into the programs regulating their recruitment and maintenance within the CNS.

AB - T cell surveillance is mandatory for maintaining central nervous system (CNS) homeostasis, while aberrant accumulation is linked to neuroinflammation. To explore the residency programs acquired by T cells through different anatomical locations of the human brain, we isolated CD8+ and CD4+ T cells from CNS border compartments (choroid plexus and leptomeninges), intrathecal compartments (cerebrospinal fluid [CSF] and subcortical white matter [WM]), and paired peripheral blood of brain donors. Flow cytometry revealed a shared effector memory phenotype across CNS compartments that was partially induced in circulating T cells interacting with brain endothelium in vitro. Intrathecal T cells expressed full tissue-residency traits, yet T cells from WM, compared to CSF, showed reduced expression of migratory, co-stimulatory, and recent activation markers despite a similar cytokine response upon ex vivo activation. This work demonstrates the versatility of T cell phenotypes across CNS compartments and provides insight into the programs regulating their recruitment and maintenance within the CNS.

U2 - 10.1016/j.celrep.2025.115960

DO - 10.1016/j.celrep.2025.115960

M3 - Article

C2 - 40638384

SN - 2211-1247

VL - 44

SP - 115960

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -