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<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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月14日

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  • Antoine Freuchet,
  • Emil Johansson,
  • April Frazier,
  • Irene Litvan,
  • Jennifer G. Goldman,
  • Roy N. Alcalay,
  • David Sulzer,
  • Cecilia S. Lindestam Arlehamn,
  • Alessandro Sette

摘要

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.