Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synuclein
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 previ...
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Nature Portfolio
2025-05-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-00981-6 |
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| author | Antoine Freuchet Emil Johansson April Frazier Irene Litvan Jennifer G. Goldman Roy N. Alcalay David Sulzer Cecilia S. Lindestam Arlehamn Alessandro Sette |
| author_facet | Antoine Freuchet Emil Johansson April Frazier Irene Litvan Jennifer G. Goldman Roy N. Alcalay David Sulzer Cecilia S. Lindestam Arlehamn Alessandro Sette |
| author_sort | Antoine Freuchet |
| collection | DOAJ |
| description | 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 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. |
| format | Article |
| id | doaj-art-6c8e6e4828f641b8a6429e3e4d2d1d70 |
| institution | Kabale University |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-6c8e6e4828f641b8a6429e3e4d2d1d702025-08-20T03:46:03ZengNature Portfolionpj Parkinson's Disease2373-80572025-05-011111910.1038/s41531-025-00981-6Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synucleinAntoine Freuchet0Emil Johansson1April Frazier2Irene Litvan3Jennifer G. Goldman4Roy N. Alcalay5David Sulzer6Cecilia S. Lindestam Arlehamn7Alessandro Sette8Center for Autoimmunity and Inflammation, La Jolla Institute for ImmunologyCenter for Autoimmunity and Inflammation, La Jolla Institute for ImmunologyCenter for Autoimmunity and Inflammation, La Jolla Institute for ImmunologyDepartment of Neuroscience, University of California San DiegoJPG Enterprises LLC; prior: Shirley Ryan Ability Lab and Northwestern University Feinberg School of MedicineDepartment of Neurology, Columbia University Irving Medical CenterAligning Science Across Parkinson’s (ASAP) Collaborative Research NetworkCenter for Autoimmunity and Inflammation, La Jolla Institute for ImmunologyCenter for Autoimmunity and Inflammation, La Jolla Institute for ImmunologyAbstract 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.https://doi.org/10.1038/s41531-025-00981-6 |
| spellingShingle | Antoine Freuchet Emil Johansson April Frazier Irene Litvan Jennifer G. Goldman Roy N. Alcalay David Sulzer Cecilia S. Lindestam Arlehamn Alessandro Sette Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synuclein npj Parkinson's Disease |
| title | Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synuclein |
| title_full | Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synuclein |
| title_fullStr | Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synuclein |
| title_full_unstemmed | Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synuclein |
| title_short | Differential memory enrichment of cytotoxic CD4 T cells in Parkinson’s disease patients reactive to α-synuclein |
| title_sort | differential memory enrichment of cytotoxic cd4 t cells in parkinson s disease patients reactive to α synuclein |
| url | https://doi.org/10.1038/s41531-025-00981-6 |
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