T cells and Parkinson’s: What we know and where we are going
While Parkinson’s disease (PD) is classically considered a movement disorder, in recent decades non-motor symptoms have become recognized as integral to the disease process. While research efforts have focused on the loss of neurons in the brain and understanding mechanisms behind Lewy body formation, the core feature of PD, exciting and emerging research has highlighted the role of the immune system in the pathogenesis and progression of PD. Recent clinical studies and studies in animal models have indicated that immune dysfunction, particularly evidence of neuroinflammation, or inflammation in the central nervous system (CNS) occurs early (Ref 1) and potentially persists throughout disease progression (Ref 2&3). Neuroinflammation is an important and fundamental process by which the immune system in the brain responds to injury or infection. Classically, immune responses can be divided into innate and adaptive responses. Innate immunity is mediated early (within minutes to hours) by phagocytic cells, primarily macrophages and microglia in the brain, while adaptive immunity is highly specialized and slower to respond (days later) and is mediated by T and B lymphocytes. All these cells reside within the CNS in healthy PERSONS and in neurodegenerative diseases like PD and Alzheimer’s disease. While previous WPC blogs have discussed the overview of inflammation in PD (Ref 4), the focus of this blog post will be about a specific subset of adaptive immune cells, T lymphocytes, and their role in PD.
Overview of T Lymphocytes (T cells)
T lymphocytes (also known as T cells) are a subset of white blood cells critical to the adaptive immune response. T cells are classified into two main types: CD4 helper T cells and CD8 cytotoxic T cells. CD4 helper T cells coordinate immune responses by secreting chemical messengers called cytokines that activate other immune cells into action, while CD8 cytotoxic T cells directly destroy infected or damaged cells. In health and disease, T cells circulate in the blood and lymphatic system, surveying for antigens presented by major histocompatibility complex (MHC) molecules. Upon recognizing a specific antigen, they become activated, proliferate, and execute their effector functions including cytokine release and destroying damaged or infected cells. Under normal conditions, the brain or CNS has a very small number of T cells that primarily reside in the meninges and cerebrospinal fluid that surrounds the brain, however, in neurodegenerative disease including PD this privilege appears to be compromised as T cells can readily infiltrate into the brain.
Evidence of T Cell Involvement in PD
One of the foundational discoveries in 2009 was the identification of T cell infiltration into the brain and cerebrospinal fluid of persons with PD (Ref 5). Analysis of PD brains revealed the presence of both CD4 helper and CD8 cytotoxic T cells in the substantia nigra, surrounding or in proximity to degenerating dopaminergic neurons, a hallmark of PD. This finding was critical as it implicated for the first time, that the adaptive immune system, particularly T cells may be important for mediating the death of neurons in PD. Further supporting this, several follow up studies have demonstrated altered T cell populations in the blood of individuals with PD. These changes include a decrease in regulatory T cells (Tregs), which function to suppress inappropriate immune responses, suggesting a possible dysregulation of T cell responses in PD (reviewed in ref 6). Conversely, additional studies also found increases in pro-inflammation CD4 T cell subsets, which are known to secrete cytokines that can exacerbate inflammation in the CNS and contribute to neuronal damage (reviewed in ref 6&7).
Mechanisms of T Cell-Mediated Neurodegeneration
The mechanisms by which T cells directly contribute to PD are not well understood and a focus of current research in my laboratory and others. One of the primary hypotheses involves the recognition of alpha-synuclein as an antigen by the immune system, as alpha-synuclein is the primary protein implicated in Lewy bodies in the brain and suggesting why PD could have autoimmune-like features. Our work and others have shown that alpha-synuclein may be processed by innate immune cells, microglia or macrophages, in the brain and presented to CD4 helper T cells via MHC class II molecules (Ref 8&9). In support, genetic studies have identified associations between PD and certain human leukocyte antigen (HLA) alleles, or MHC class II molecules, implying that antigen presentation to CD4 T cells could be a critical step in disease progression (Ref 10 and reviewed in Ref 11). Utilizing a rodent model of PD where alpha-synuclein is expressed in neurons in the substantia nigra, we were able to show that CD4 T cells mediate the degeneration of neurons leading to PD like pathology (Ref 12). In human studies, T cells recognizing alpha-synuclein were shown to become activated, releasing pro-inflammatory cytokines. Furthermore, these alpha-synuclein peptides were predicted to bind to HLA alleles, or MHC molecules that are associated with genetic risk of PD (Ref 13).
It is important to note that CD8 T cells may also play a direct cytotoxic role. Studies in mouse and human inducible pluripotent stem cell (iPSC) models have shown that dopaminergic neurons can aberrantly express MHC class I molecules under inflammatory conditions, making them susceptible to CD8 T cell-mediated attack (Ref 14). In support, CD8 T cells are the most common T cell found to reside in the brain and blood brain barrier of persons with PD (Ref 15). This critical work suggests that neurons may become unintended targets of the adaptive immune system.
Therapeutic Implications-the way of the future?
A critical challenge for the development of immunomodulatory therapies lies in distinguishing dysregulated or maladaptive immune responses from helpful or protective ones. As some T cell-mediated actions may be beneficial, such as dampening harmful inflammation or promoting tissue repair. Current research has shifted to focus on longitudinal studies aimed to track immune changes, particularly T cell changes throughout disease progression or over time. This would give researchers and clinicians a more accurate picture of how the immune dynamic changes over time in persons with PD. In addition to animal model studies, this critical research aimed to understand the disease-driving role of T cells in PD opens new, highly specialized routes for therapeutic intervention in PD involving the immune system (reviewed in Ref 16). It also opens the possibility to reuse or repurpose current approved drugs for neuroinflammatory or autoimmune disorders like multiple sclerosis. Immune modifying drugs or strategies that aim to suppress T cell responses or enhance regulatory pathways (T reg) could offer benefits that may halt disease progression. In support, there are many clinical trials ongoing either directly targeting or indirectly targeting the immune system that may have action on T cells, and currently approved therapeutics for T cells in diseases such as cancer.
Overall, T cells have emerged as key players in PD. Mounting clinical and research evidence suggests they contribute to harmful neuroinflammation that contributes to neuronal loss in the brain, particularly the substantia nigra. T cell interactions with alpha-synuclein, innate immune cells in the brain such as microglia, and directly with neurons underscore a complex relationship and challenge our traditional views of PD as a purely neurological disorder and highlights the need for immunomodulatory therapies in the future.
For more information, please see the references below:
References:
1. Yacoubian TA, Fang YD, Gerstenecker A, Amara A, Stover N, Ruffrage L, Collette C, Kennedy R, Zhang Y, Hong H, Qin H, McConathy J, Benveniste EN, Standaert DG. Brain and Systemic Inflammation in De Novo Parkinson's Disease. Mov Disord. 2023 May;38(5):743-754. doi: 10.1002/mds.29363. Epub 2023 Feb 28. PMID: 36853618; PMCID: PMC11403348.
2. Harms AS, Yang YT, Tansey MG. Central and peripheral innate and adaptive immunity in Parkinson's disease. Sci Transl Med. 2023 Nov 8;15(721):eadk3225. doi: 10.1126/scitranslmed.adk3225. Epub 2023 Nov 8. PMID: 37939158.
3. Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol. 2022 Nov;22(11):657-673. doi: 10.1038/s41577-022-00684-6. Epub 2022 Mar 4. PMID: 35246670; PMCID: PMC8895080.
4. https://www.worldpdcongress.org/home/2024/11/13/inflammation-in-parkinsons-disease)
5. Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 2009 Jan;119(1):182-92. doi: 10.1172/JCI36470. Epub 2008 Dec 22. PMID: 19104149; PMCID: PMC2613467.
6. Harms AS, Ferreira SA, Romero-Ramos M. Periphery and brain, innate and adaptive immunity in Parkinson's disease. Acta Neuropathol. 2021 Apr;141(4):527-545. doi: 10.1007/s00401-021-02268-5. Epub 2021 Feb 8. PMID: 33555429; PMCID: PMC7952334.
7. Garretti F, Agalliu D, Lindestam Arlehamn CS, Sette A, Sulzer D. Autoimmunity in Parkinson's Disease: The Role of α-Synuclein-Specific T Cells. Front Immunol. 2019 Feb 25;10:303. doi: 10.3389/fimmu.2019.00303. PMID: 30858851; PMCID: PMC6397885.Ref 7:
8. Harms AS, Cao S, Rowse AL, Thome AD, Li X, Mangieri LR, Cron RQ, Shacka JJ, Raman C, Standaert DG. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci. 2013 Jun 5;33(23):9592-600. doi: 10.1523/JNEUROSCI.5610-12.2013. PMID: 23739956; PMCID: PMC3903980
9. Jimenez-Ferrer I, Bäckström F, Dueñas-Rey A, Jewett M, Boza-Serrano A, Luk KC, Deierborg T, Swanberg M. The MHC class II transactivator modulates seeded alpha-synuclein pathology and dopaminergic neurodegeneration in an in vivo rat model of Parkinson's disease. Brain Behav Immun. 2021 Jan;91:369-382. doi: 10.1016/j.bbi.2020.10.017. Epub 2020 Oct 22. PMID: 33223048
10. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet. 2010 Sep;42(9):781-5. doi: 10.1038/ng.642. Epub 2010 Aug 15. PMID: 20711177; PMCID: PMC2930111.
11. Jimenez-Ferrer I, Swanberg M. Immunogenetics of Parkinson’s Disease. In: Stoker TB, Greenland JC, editors. Parkinson’s Disease: Pathogenesis and Clinical Aspects [Internet]. Brisbane (AU): Codon Publications; 2018 Dec 21. Chapter 2. PMID: 30702841.
12. Williams GP, Schonhoff AM, Jurkuvenaite A, Gallups NJ, Standaert DG, Harms AS. CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson's disease. Brain. 2021 Aug 17;144(7):2047-2059. doi: 10.1093/brain/awab103. PMID: 33704423; PMCID: PMC8370411.
13. Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A. T cells from patients with Parkinson's disease recognize α-synuclein peptides. Nature. 2017 Jun 29;546(7660):656-661. doi: 10.1038/nature22815. Epub 2017 Jun 21. Erratum in: Nature. 2017 Sep 13;549(7671):292. doi: 10.1038/nature23896. PMID: 28636593; PMCID: PMC5626019.
14. Cebrián C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, Kanter E, Budhu S, Mandelbaum J, Vonsattel JP, Zecca L, Loike JD, Sulzer D. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun. 2014 Apr 16;5:3633. doi: 10.1038/ncomms4633. PMID: 24736453; PMCID: PMC4024461.
15. Galiano-Landeira J, Torra A, Vila M, Bové J. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson's disease. Brain. 2020 Dec 1;143(12):3717-3733. doi: 10.1093/brain/awaa269. PMID: 33118032.
Ashley S. Harms, PhD is an associate professor at the University of Alabama at Birmingham (USA) in the Department of Neurology and the Center for neurodegeneration and Experimental Therapeutics.. She has spoken at past World Parkinson Congresses and has sat on the WPC Scientific Program Committee twice. Professor Harms will join the WPC Research Spotlight 2025 series on Tuesday, June 3, 2025. Register here for the series.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not reflect the opinions or positions of the World Parkinson Coalition®