Single-cell transcriptomics reveals the interaction between peripheral CD4⁺ CTLs and mesencephalic endothelial cells mediated by IFNG in Parkinson's disease

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.