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T cells from patients with Parkinson’s disease recognize α-synuclein peptides

Nature volume 546, pages 656–661 (2017)Cite this article

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An Erratum to this article was published on 14 September 2017

Abstract

Genetic studies have shown the association of Parkinson’s disease with alleles of the major histocompatibility complex1,2,3. Here we show that a defined set of peptides that are derived from α-synuclein, a protein aggregated in Parkinson’s disease4, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson’s disease. These responses may explain the association of Parkinson’s disease with specific major histocompatibility complex alleles.

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Figure 1: α-syn autoimmune responses are directed against two regions.
Figure 2: Reactivity to native and modified α-syn peptides in patients with Parkinson’s disease.
Figure 3: HLA association of the Y39 epitope and identification of A*11:01 restricted 9–10 a.a. length Y39 epitopes.

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Acknowledgements

Supported by the JPB (D.S., T.M.D), William F. Richter (D.S.), Michael J. Fox (A.S., D.S.) and Parkinson’s Foundations (A.S., D.S.). X.M., V.L.D. and T.M.D. are supported by NIH/NINDS grant P50 NS38377. X.M. is supported by NIA ADRC P50AG005146. T.M.D. is the Abramson Professor. X.M., V.L.D. and T.M.D. acknowledge joint support by AHMMRF, JHH and JHUSOM Parkinson’s disease program, M-2014.

Author information

Authors and Affiliations

  1. Departments of Psychiatry, Division of Molcular Therapeutics, Columbia University, New York State Psychiatric Institute, New York, 10032, New York, USA

    David Sulzer, Francesca Garretti, Ellen Kanter, Julian Agin-Liebes, Elizabeth Phillips & Simon Mallal

  2. Department of Neurology, Columbia University, New York, 10032, New York, USA

    David Sulzer, Roy N. Alcalay, Lucien Cote, Christopher Liong, Elizabeth Phillips & Simon Mallal

  3. Department of Pharmacology, Columbia University, New York, 10032, New York, USA

    David Sulzer

  4. Department of Microbiology and Immunology, University of Oklahoma, Oklahoma City, 73104, Oklahoma, USA

    Curtis McMurtrey & William H. Hildebrand

  5. Institute for Cell Engineering and the Department of Neurology, Neuroregeneration and Stem Cell Program, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Xiaobo Mao, Valina L. Dawson & Ted M. Dawson

  6. Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, 70130-2685, USA

    Xiaobo Mao, Valina L. Dawson & Ted M. Dawson

  7. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Valina L. Dawson

  8. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Valina L. Dawson & Ted M. Dawson

  9. Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Ted M. Dawson

  10. Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, 92037, California, USA

    Carla Oseroff, John Pham, John Sidney, Myles B. Dillon, Chelsea Carpenter, Daniela Weiskopf, Bjoern Peters, April Frazier, Cecilia S. Lindestam Arlehamn & Alessandro Sette

  11. Institute for Immunology and Infectious Diseases, Murdoch University, Perth, 6150, Western Australia, Australia

    Elizabeth Phillips & Simon Mallal

Authors
  1. David Sulzer
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Contributions

D.S. and A.S. conceived the study and wrote the paper. C.S.L.A. and F.G. contributed to writing and prepared figures. R.N.A. and L.C. recruited participants and performed clinical evaluations. C.L., J.A.-L. and A.F. maintained patient data and assisted in subject recruitment. E.K. arranged tissue handling and maintained records. F.G., C.O., J.P., M.B.D., C.C., D.W., E.P., S.M., B.P., W.H.H., C.M. and C.S.L.A. conducted analyses of T cells and antigenic epitopes. X.M., V.L.D. and T.M.D. prepared and characterized α-syn proteins and fibrils. J.S. performed in vitro MHC-binding assays.

Corresponding authors

Correspondence to David Sulzer or Alessandro Sette.

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Competing interests

Columbia University filed a patent application for the use of α-syn peptides as biomarkers (US patent application number 15/300,713). D.S. (Columbia University) and A.S. (La Jolla Institute for Allergy and Immunology) are listed as inventors.

Additional information

Reviewer Information Nature thanks M. Tansey and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Vanderbilt University School of Medicine, Nashville, Tennessee 37235, USA

Extended data figures and tables

Extended Data Figure 1 T cell reactivity against (wild-type and post-translationally modified) α-syn peptides.

Magnitude of responses, expressed as the total magnitude (SFC per 106 PBMCs) of response per peptide and participant combination. Responses against any α-syn 15-mer peptide spanning S129 and Y39, ‘any peptide’, Parkinson’s disease (n = 209), control (n = 132); and responses against individual α-syn 15-mer peptides spanning S129 and Y39. Each dot represents a peptide and participant combination. Closed circles, Parkinson’s disease (n = 19); open circles, control (n = 12). Two-tailed Mann–Whitney U-test, *P < 0.05, **P < 0.01, ***P < 0.001. a, IFNγ response. b, IL-5 response. c, Total (IFNγ and IL-5 combined) response.

Source data

Extended Data Figure 2 Characterization of α-syn-specific responses in Parkinson’s disease.

a, Gating strategy. T cells were gated based on CD3 expression. Boolean gating was used to define cytokine-producing cells expressing CD4 and/or CD8. b, Percentage of total cytokine detected from CD3+ T cells in response to α-syn peptides. Each point represents one participant (n = 9); mean ± s.d. are indicated. Dotted line indicates 0.05% cut-off for specific cytokine production by CD3+ T cells. c, Percentage of responding T cells that produce each cytokine, IFNγ, IL-4, IL-10 and IL-17. Each point represents one participant that exceeded the cut-off (n = 6), mean ± s.d. are indicated. d, Percentage of responding T cells that are CD4+, CD8+, CD4−CD8−, or CD4+CD8+ T cells. Each point represents one participant (n = 6), mean ± s.d. are indicated.

Source data

Extended Data Figure 3 Specific T cell reactivity against native or fibrilized α-syn.

Magnitude of responses, expressed as the average spots per 106 PBMC, of response per protein and participant with Parkinson’s disease or peptide and participant with Parkinson’s disease combination (n = 12 Parkinson’s disease participants, each represented by a different symbol). The lines connect discrete values from each individual participant and are present to provide a means to compare responses within and between individuals. The difference between response to unstimulated compared to peptides, the native α-syn and PFF groups is significant by the Wilcoxon signed-rank one-tailed test (values are shown in the figure). No significant difference (Wilcoxon signed-rank two-tailed test) in response to PFF and native protein was apparent in this relatively small sample.

Source data

Extended Data Figure 4 HLA-DR surface expression across DRB1*15:01+ or DRB1*15:01− participants with Parkinson’s disease and healthy controls.

a, Gating strategy for FACS analysis. After eliminating non-lymphocytes and doublet cells by forward- and side-scatter, cells were gated based on HLA-DR expression. b–e, HLA-DR and CD3 expression of cells from participants (black, HLA-DR antibody; red, isotype control) with Parkinson’s disease that carry (b; n = 5) and do not carry (c; n = 5) the DRB1*15:01 allele and healthy controls (HC) that carry (d; n = 3) and do not carry (e; n = 5) the DRB1*15:01 allele. f, g, 721.221 (f) and RM3 (g) cells are used as controls that do not and do express HLA class II, respectively. h, Mean fluorescent intensities (MFI) ± s.d. of HLA-DR expression for each participant cohort. i, Percentage of living cells that express HLA-DR. Data are mean ± s.d.

Source data

Extended Data Figure 5 HLA class I surface expression across DRB1*15:01+ or DRB1*15:01− participants with Parkinson’s disease and healthy controls.

a, Gating strategy for FACS analysis. After eliminating non-lymphocytes and doublet cells by forward- and side-scatter, cells were gated based on HLA-ABC expression. b–e, HLA-ABC and CD3 expression of cells from participants (black, HLA-ABC antibody; red, isotype control) with Parkinson’s disease that carry (b; n = 5) and do not carry (c; n = 5) the DRB1*15:01 allele and healthy controls that carry (d; n = 3) and do not carry (e; n = 5) the DRB1*15:01 allele. f, g, 721.221 (f) and RM3 (g) cells are used as controls that do not and do express HLA class I, respectively. (h) Mean fluorescent intensities (MFI) ± s.d. of HLA-ABC expression for each participant cohort.

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Sulzer, D., Alcalay, R., Garretti, F. et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546, 656–661 (2017). https://doi.org/10.1038/nature22815

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