Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synuclein

Freuchet, Antoine ; Johansson, Emil LU orcid ; Frazier, April ; Litvan, Irene ; Goldman, Jennifer G. ; Alcalay, Roy N. ; Sulzer, David ; Lindestam Arlehamn, Cecilia S. and Sette, Alessandro (2025) In npj Parkinson's Disease 11(1).
Abstract

Parkinson’s disease (PD) is a complex neurodegenerative disease with a largely unknown etiology. Although the loss of dopaminergic neurons in the substantia nigra pars compacta is the pathological hallmark of PD, neuroinflammation also plays a fundamental role in PD pathology. We have previously reported that PD patients have increased frequencies of T cells reactive to peptides from α-synuclein (α-syn). However, not all PD participants respond to α-syn. Furthermore, we have previously found that CD4 T cells from PD participants responding to α-syn (PD_R) are transcriptionally distinct from PD participants not responding to α-syn (PD_NR). To gain further insight into the pathology of PD_R participants, we investigated surface protein... (More)

Parkinson’s disease (PD) is a complex neurodegenerative disease with a largely unknown etiology. Although the loss of dopaminergic neurons in the substantia nigra pars compacta is the pathological hallmark of PD, neuroinflammation also plays a fundamental role in PD pathology. We have previously reported that PD patients have increased frequencies of T cells reactive to peptides from α-synuclein (α-syn). However, not all PD participants respond to α-syn. Furthermore, we have previously found that CD4 T cells from PD participants responding to α-syn (PD_R) are transcriptionally distinct from PD participants not responding to α-syn (PD_NR). To gain further insight into the pathology of PD_R participants, we investigated surface protein expression of 11 proteins whose genes had previously been found to be differentially expressed when comparing PD_R and healthy control participants not responding to α-syn (HC_NR). We found that Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) was expressed on a significantly higher proportion of CD4 effector memory T cells (TEM) in PD_R compared to HC_NR. Single-cell RNA sequencing analysis of cells expressing or not expressing CELSR2 revealed that PD_R participants have elevated frequencies of activated TEM subsets and an almost complete loss of cytotoxic TEM cells. Flow cytometry analyses confirmed that Granulysin+ CD4 cytotoxic TEM cells are reduced in PD_R. Taken together, these results provide further insight into the perturbation of T cell subsets in PD_R, and highlights the need for further investigation into the role of Granulysin+ CD4 cytotoxic TEM in PD pathology.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
npj Parkinson's Disease
volume
11
issue
1
article number
127
publisher
Springer Nature
external identifiers
  • scopus:105005409895
ISSN
2373-8057
DOI
10.1038/s41531-025-00981-6
language
English
LU publication?
yes
id
424899c0-5e96-45c4-9b2e-6a59a88bf5b7
date added to LUP
2025-07-14 10:53:46
date last changed
2025-07-14 10:54:09
@article{424899c0-5e96-45c4-9b2e-6a59a88bf5b7,
  abstract     = {{<p>Parkinson’s disease (PD) is a complex neurodegenerative disease with a largely unknown etiology. Although the loss of dopaminergic neurons in the substantia nigra pars compacta is the pathological hallmark of PD, neuroinflammation also plays a fundamental role in PD pathology. We have previously reported that PD patients have increased frequencies of T cells reactive to peptides from α-synuclein (α-syn). However, not all PD participants respond to α-syn. Furthermore, we have previously found that CD4 T cells from PD participants responding to α-syn (PD_R) are transcriptionally distinct from PD participants not responding to α-syn (PD_NR). To gain further insight into the pathology of PD_R participants, we investigated surface protein expression of 11 proteins whose genes had previously been found to be differentially expressed when comparing PD_R and healthy control participants not responding to α-syn (HC_NR). We found that Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) was expressed on a significantly higher proportion of CD4 effector memory T cells (T<sub>EM</sub>) in PD_R compared to HC_NR. Single-cell RNA sequencing analysis of cells expressing or not expressing CELSR2 revealed that PD_R participants have elevated frequencies of activated T<sub>EM</sub> subsets and an almost complete loss of cytotoxic T<sub>EM</sub> cells. Flow cytometry analyses confirmed that Granulysin<sup>+</sup> CD4 cytotoxic T<sub>EM</sub> cells are reduced in PD_R. Taken together, these results provide further insight into the perturbation of T cell subsets in PD_R, and highlights the need for further investigation into the role of Granulysin<sup>+</sup> CD4 cytotoxic T<sub>EM</sub> in PD pathology.</p>}},
  author       = {{Freuchet, Antoine and Johansson, Emil and Frazier, April and Litvan, Irene and Goldman, Jennifer G. and Alcalay, Roy N. and Sulzer, David and Lindestam Arlehamn, Cecilia S. and Sette, Alessandro}},
  issn         = {{2373-8057}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Springer Nature}},
  series       = {{npj Parkinson's Disease}},
  title        = {{Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synuclein}},
  url          = {{http://dx.doi.org/10.1038/s41531-025-00981-6}},
  doi          = {{10.1038/s41531-025-00981-6}},
  volume       = {{11}},
  year         = {{2025}},
}