CD4+ T cells contribute to neurodegeneration in Lewy body dementia [CSF_and_PBMCs_Healthy and LBD]

Recent studies indicate that the adaptive immune system plays a role in Lewy body dementia (LBD). However, the mechanism regulating T cell brain homing in LBD is unknown. Here, we observed T cells adjacent to Lewy bodies and dopaminergic neurons in post-mortem LBD brains. Single-cell RNA sequencing of cerebrospinal fluid (CSF) 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. Furthermore, we observed clonal expansion and upregulated Interleukin 17A expression by CD4+ T cells stimulated with a phosphorylated α-synuclein epitope. Thus, CXCR4-CXCL12 signaling may represent a mechanistic target for inhibiting pathological interleukin-17-producing T cell trafficking in LBD. scRNAseq of CSF cells from healthy (n=11) and LBD (n=11) subjects. Live cells were sorted with a live/dead SYTOX blue dye. Sequencing libraries were prepared using the 10X Genomics platform. PBMCs from some of these subjects were also sequenced by scRNAseq.