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CD4+ T cells contribute to neurodegeneration in Lewy body dementia
Science  (IF47.728),  Pub Date : 2021-10-14, DOI: 10.1126/science.abf7266
David Gate, Emma Tapp, Olivia Leventhal, Marian Shahid, Tim J. Nonninger, Andrew C. Yang, Katharina Strempfl, Michael S. Unger, Tobias Fehlmann, Hamilton Oh, Divya Channappa, Victor W. Henderson, Andreas Keller, Ludwig Aigner, Douglas R. Galasko, Mark M. Davis, Kathleen L. Poston, Tony Wyss-Coray

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 up-regulated 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 up-regulated 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.