CD4+ T cells contribute to neurodgeneration in Lewy Body dementia

Recent studies indicate a role of the adaptive immune system in Lewy body dementia (LBD). However, the mechanisms regulating T cell brain homing in LBD remain unknown. Here, we demonstrate interaction of T cells with Lewy bodies and with dopaminergic neurons in post-mortem LBD brains. Single cell RNA sequencing of cerebrospinal fluid (CSF) cells identified upregulated expression of C-X-C Motif Chemokine Receptor 4 (CXCR4) in CD4+ T cells in LBD. CSF protein levels of the CXCR4 ligand, C-X-C Motif Chemokine Ligand 12 (CXCL12) were associated with neuroaxonal damage in LBD. Finally, we demonstrate clonal expansion and upregulated Interleukin 17A by CD4+ T cells stimulated with phosphorylated a-synuclein. Cumulatively, these results indicate CXCR4-CXCL12 signaling as a mechanistic target for inhibiting pathological T cell trafficking in LBD. Overall design: Examination of transcriptional profile of cells from the cerbrospinal fluid of healthy and diseased patients