CD4+ T cells contribute to neurodegeneration in Lewy body dementia

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

doi:10.1126/science.abf7266

CD4⁺ T cells contribute to neurodegeneration in Lewy body dementia

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^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

123 Scopus citations

Abstract

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 postmortem 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 a-synuclein epitope. Thus, CXCR4-CXCL12 signaling may represent a mechanistic target for inhibiting pathological interleukin-17-producing T cell trafficking in LBD.

Original language	English (US)
Pages (from-to)	868-874
Number of pages	7
Journal	Science
Volume	374
Issue number	6569
DOIs	https://doi.org/10.1126/science.abf7266
State	Published - Nov 12 2021

Funding

This work was supported by a National Institute of Neurologic Disease and Stroke K99/R00 Pathway to Independence Award (NS112458-01A1) (D.G.); an Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging (D.G.); a National Institutes of Health National Institute on Aging (NIA) F32 Fellowship (AG055255-01A1) (D.G.); the FFG Momentia Project 867741 (L.A.); Austrian Science Fund (FWF) Project P 31362- B34 (L.A.); FFG Project 867741 PMU FFF E-20/32/169-UNG (L.A.); the Howard Hughes Medical Institute (M.M.D.); NIH U19 AG065156, R01 NS115114, P30 AG066515, and P50 NS062684 (K.L.P.); Michael J. Fox Foundation for Parkinson's Research Grants 020756, 16921, and 18411 (K.L.P.); the Lewy Body Dementia Association (K.L.P.); Alzheimer's Drug Discovery Foundation (K.L.P.); Sanofi US Services, Inc. (K.L.P.); the Cure Alzheimer's Fund (T.W.-C.); the NOMIS Foundation (T.W.-C.); NIA R01 AG045034 05 (T.W.-C.); and the NIA-funded Stanford Alzheimer's Disease Research Center P50AG047366 (V.W.H.).

ASJC Scopus subject areas

General

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10.1126/science.abf7266

Cite this

Gate, D., Tapp, E., Leventhal, O., Shahid, M., Nonninger, T. J., Yang, A. C., Strempfl, K., Unger, M. S., Fehlmann, T., Oh, H., Channappa, D., Henderson, V. W., Keller, A., Aigner, L., Galasko, D. R., Davis, M. M., Poston, K. L., & Wyss-Coray, T. (2021). CD4⁺ T cells contribute to neurodegeneration in Lewy body dementia. Science, 374(6569), 868-874. https://doi.org/10.1126/science.abf7266

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title = "CD4+ T cells contribute to neurodegeneration in Lewy body dementia",

abstract = "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 postmortem 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 a-synuclein epitope. Thus, CXCR4-CXCL12 signaling may represent a mechanistic target for inhibiting pathological interleukin-17-producing T cell trafficking in LBD.",

author = "David Gate and Emma Tapp and Olivia Leventhal and Marian Shahid and Nonninger, {Tim J.} and Yang, {Andrew C.} and Katharina Strempfl and Unger, {Michael S.} and Tobias Fehlmann and Hamilton Oh and Divya Channappa and Henderson, {Victor W.} and Andreas Keller and Ludwig Aigner and Galasko, {Douglas R.} and Davis, {Mark M.} and Poston, {Kathleen L.} and Tony Wyss-Coray",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2021",

month = nov,

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doi = "10.1126/science.abf7266",

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Gate, D, Tapp, E, Leventhal, O, Shahid, M, Nonninger, TJ, Yang, AC, Strempfl, K, Unger, MS, Fehlmann, T, Oh, H, Channappa, D, Henderson, VW, Keller, A, Aigner, L, Galasko, DR, Davis, MM, Poston, KL & Wyss-Coray, T 2021, 'CD4⁺ T cells contribute to neurodegeneration in Lewy body dementia', Science, vol. 374, no. 6569, pp. 868-874. https://doi.org/10.1126/science.abf7266

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AU - Gate, David

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AU - Shahid, Marian

AU - Nonninger, Tim J.

AU - Yang, Andrew C.

AU - Strempfl, Katharina

AU - Unger, Michael S.

AU - Fehlmann, Tobias

AU - Oh, Hamilton

AU - Channappa, Divya

AU - Henderson, Victor W.

AU - Keller, Andreas

AU - Aigner, Ludwig

AU - Galasko, Douglas R.

AU - Davis, Mark M.

AU - Poston, Kathleen L.

AU - Wyss-Coray, Tony

PY - 2021/11/12

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