In on the ground floor: T cells respond to α-synuclein in preclinical Parkinson’s disease

Analysis of peripheral blood mononuclear cells demonstrated that α-synuclein–specific T cells are active in preclinical and early Parkinson’s disease. Inflammation is a prominent feature of multiple neurodegenerative diseases including Parkinson’s disease (PD). However, the specific temporal and causal relationships between neurodegeneration, inflammation, and protein aggregates that often characterize neurodegenerative disorders are less clear. Multiple lines of evidence have implicated the innate and adaptive immune system in the pathophysiology of PD, and a previous study found T cells that recognize α-synuclein (αSyn) in blood from patients with PD. Now, Lindestam Arlehamn et al. demonstrated that αSyn-specific T cells are present in patients with PD in early stages of the disease, suggesting that adaptive immunity plays an upstream role in PD. The authors cultured peripheral blood mononuclear cells (PBMCs) from healthy controls and patients with PD, including one participant with PD who had banked PBMCs years before motor symptom onset for an unrelated purpose. They then challenged the cultured PBMCs with αSyn peptides from their previously described T cell epitope and measured the cytokine response. Among their findings, they report αSyn-specific T cell responses in the single patient more than 10 years before symptom onset and a higher magnitude of cytokine response in response to αSyn peptide challenge in 96 other patients with PD compared with controls. Interestingly, αSyn-specific T cell reactivity was more robust closer to the time of symptom onset and appeared to decline over time after PD diagnosis. Furthermore, they reported that distinct populations of T cells produced various cytokines in response to αSyn peptide challenge, including interferon-γ (IFN-γ), interleukin-4 (IL-4), and IL-10. These findings illustrate the complexity of the adaptive immune response in PD and make the case for additional studies. The authors suggest that the apparent waning of T cell reactivity as the disease progresses could indicate a pathogenic role for T cell involvement, but they also note that the production of IL-10 by αSyn-reactive T cells may point to more subtle or complex regulatory mechanisms. These findings add to the growing intrigue over the immune system and neurodegenerative disease and raise the tantalizing possibility that early intervention via modulation of T cell activity could perhaps be leveraged as a disease-modifying therapy for PD.