Single-cell transcriptomics reveals the interaction between peripheral CD4⁺ CTLs and mesencephalic endothelial cells...

Parkinson's disease (PD) is characterized by dopaminergic neurons degeneration in the substantia nigra pars compacta. Increasing evidence indicates that peripheral CD4⁺ T cells, a vital pathological component of PD, have been implicated in systemic inflammation activation, blood-brain barrier (BBB) dysfunction, central nervous system infiltration, and consequent neurons degeneration. However, there is no consensus on CD4⁺ T cell types' exact phenotypic characteristics in systemic inflammation and the mechanism of CD4⁺ T cells traffic into the BBB in patients with PD. In this study, we employed single-cell RNA sequencing (scRNA-seq) to elucidate the potential mechanism of T cells on the breakdown of BBB. The PD-associated Cytotoxic CD4⁺ T cells (CD4⁺ CTLs) were characterized by a significant increase in proportion as well as enhancement of interferon-gamma (IFNG) response and cell adhesion. Meanwhile, TBX21, IRF1 and NFATC2, identified as the key transcription factors in effector CD4⁺ T cells differentiation, induced overexpression of target genes-IFNG in CD4⁺ CTLs. Interestingly, endothelial cells (ECs) in PD patients were discovered to be more responsive to IFNG than other cell types of midbrain. Furthermore, the cell-cell communication analysis between CD4⁺ T cells and midbrain cells identified IFNG/IFNGR1 and SPP1/ITGB1 as the ligand-receptor pairs to mediate CD4⁺ CTLs' infiltration into the central nervous system (CNS) through the weakened ECs' tight junction. Together, these results suggested that PD-specific peripheral CD4⁺ CTLs might influence BBB function by migrating to mesencephalic endothelial cells (ECs) and activating the IFNG response in ECs.