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. 2017 Jun 29;546(7660):656-661.
doi: 10.1038/nature22815. Epub 2017 Jun 21.

T Cells From Patients With Parkinson's Disease Recognize α-Synuclein Peptides

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Free PMC article

T Cells From Patients With Parkinson's Disease Recognize α-Synuclein Peptides

David Sulzer et al. Nature. .
Free PMC article

Erratum in

  • Erratum: T cells from patients with Parkinson's disease recognize α-synuclein peptides.
    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, Arlehamn CSL, Sette A. Sulzer D, et al. Nature. 2017 Sep 13;549(7671):292. doi: 10.1038/nature23896. Nature. 2017. PMID: 28905919

Abstract

Genetic studies have shown the association of Parkinson's disease with alleles of the major histocompatibility complex. Here we show that a defined set of peptides that are derived from α-synuclein, a protein aggregated in Parkinson's disease, 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.

Figures

Extended Data Figure 1
Extended Data Figure 1. T cell reactivity against α-syn peptides (wild type and post-translationally modified)
Magnitude of responses, expressed as the total magnitude (SFC/106 PBMC) of response per peptide/participant combination. Responses against any α-syn 15mer peptide spanning S129 and Y39, “any peptide”, PD (n=209), Control (n=132), and responses against individual α-syn 15mer peptides spanning S129 and Y39. Each dot represents a peptide/participant combination. Closed circles, PD (n=19); open circles, Control (n=12). Two-tailed Mann Whitney, *, p<0.05, **, p<0.01, ***, p<0.001. (A) IFNγ, (B) IL-5, (C) total (IFNγ and IL-5 combined) response.
Extended Data Figure 2
Extended Data Figure 2. Characterization of α-syn specific responses in PD
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, Percent total cytokine detected from CD3+ T cells in response to α-syn peptides. Each point represents one participant (n=9); median ± interquartile range is indicated. Dotted line indicates 0.05% cut-off for specific cytokine production by CD3+ T cells. c, Percentage of total cytokines produced for IFNγ, IL-4, IL-10, and IL-17. Each point represents one participant that exceeded the cut-off (n=6), median ± interquartile range is indicated. d, Percentage of total cytokines produced by CD4+, CD8+, CD4CD8, or CD4+CD8+ T cells. Each point represents one participant (n=6), median ± interquartile range is indicated.
Extended Data Figure 3
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/PD participant or peptide/PD participant combination (n=12 PD 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 one-tailed test (values are shown in the figure). No significant difference (Wilcoxon two-tailed test) in response to PFF and native protein was apparent in this relatively small sample.
Extended Data Figure 4
Extended Data Figure 4. HLA-DR surface expression across DRB1*15:01+ or DRB1*15:01 PD and HC participants
(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. HLA-DR and CD3 expression of participant cells (black; HLA-DR antibody, red; isotype control) of PD patients that carry (b; n=5) and do not carry (c; n=5) DRB1*15:01 allele and HC that carry (d; n=3) and do not carry (e; n=5) DRB1*15:01 allele. 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) ± standard deviations of HLA-DR expression for each participant cohort. (i) Percentage of living cells that express HLA-DR, mean ± SD.
Extended Data Figure 5
Extended Data Figure 5. HLA class I surface expression across DRB1*15:01+ or DRB1*15:01 PD and HC participants
(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. HLA-ABC and CD3 expression of participant cells (black: HLA-ABC antibody, red: isotype control) of PD patients that carry (b; n=5) and do not carry (c; n=5) DRB1*15:01 allele and HC that carry (d; n=3) and do not carry (e; n=5) DRB1*15:01 allele. 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) ± standard deviations of HLA-ABC expression for each participant cohort.
Figure 1
Figure 1. α-Syn autoimmune responses are directed against two regions
a Sequence of α-syn. Antigenic regions are highlighted with dashed red lines with amino acids Y39 and S129 in bold. (b–d) Magnitude of responses expressed as (SFC/106 PBMC) per peptide/participant combination. Left panels; response to all overlapping native α-syn 15mer peptides in PD (n=733) and Control (n=372). Right panels indicate responses against specific 15mers. Grey shading indicates antigenic region containing Y39. (e–g). Magnitude of responses. Left panels; responses to all native and phosphorylated S129 α-syn 15mer peptides in PD (n=150) and Control (n=72). Right panels; responses against specific S129 peptides. Closed circles, PD (n=19, indicated by *, all other n=25); open circles, Control (n=12 participants). Two-tailed Mann Whitney, ns, not significant. (b,e) IFNγ, (c,f) IL-5, (d,g) total (IFNγ & IL-5) response. As many participants showed no response, many points are at the limit of resolution (100 SFC).
Figure 2
Figure 2. Reactivity to native and modified α-syn peptides in PD patients
(a–c) Magnitude of responses against native and modified α-syn 15mer S129 and Y39 region peptides as (SFC/106 PBMC). Each point represents a peptide/participant combination. Closed circles, PD (n=403 peptide/participant combinations “any peptide”, KTKEGVLYVGSKTKE n=63 participants (^), modified peptides marked with * are tested in 19 participants, unmodified peptides are tested in n=41); open circles, control (n=228 any peptide, ^ n=36, *n=12 and unmodified peptides n=24)a, IFNγ, b, IL-5, c, total (IFNγ & IL-5 combined) responses. d, Combined IL-5 and IFNγ responses against individual native and modified α-syn peptides by PD. Black points, IFNγ responses; red points, IL-5 responses. Two-tailed Mann Whitney, *, p<0.05, **, p<0.01, ***, p<0.001. As many participants showed no response, many points are at the limit of resolution (100 SFC).
Figure 3
Figure 3. HLA association of Y39 epitope and identification of A*11:01 restricted 9–10aa length Y39 epitopes
a, Overlapping but largely independent associations between DRB1*15:01, DQB1*03:04 and A*11:01 for PD (13 participants) responding to the Y39 epitope. (b,c) Magnitude of responses by b, PD (n=19) and c, control participants (n=12), as (SFC/106 PBMC) of response per peptide/participant combination to α-syn 9–10mer peptides spanning the protein. In some cases, response to overlapping peptides are combined, with additional residues of the longer peptide in parentheses. b, top panel, IFNγ; middle, IL-5; bottom, total (IFNγ & IL-5 combined) response. c, Total (IFNγ & IL-5 combined). As many participants showed no T cell response, many points are at the limit of resolution (100 SFC).

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