Blood CD8+ T cell responses against myelin determinants in multiple sclerosis and healthy individuals.
Patients with multiple sclerosis (MS) display significant peripheral blood CD8(+) T cell receptor biases, suggesting clonal selection. Our objective was to identify relevant myelin-derived peptides capable of eliciting responses of fresh blood CD8+ T cells in MS patients. We focused our analysis on the HLA supertypes (HLA-A3, -A2, -B7, -B27, -B44) predominant in a patient cohort. Three myelin protein (MBP, PLP and MOG) sequences were screened for HLA binding motifs and peptides were tested for their binding to HLA molecules. The cellular responses of 27 MS patients and 19 age- and sex-matched healthy controls (HC) were tested in IFN-gamma ELISPOT assays only detecting pre-committed CD8+ T cells. Sixty-nine new epitopes elicited positive responses, with MOG-derived peptides being the most immunogenic and peptides binding to HLA-A3 being the most frequent. However, MS patients and HC displayed the same frequency of autoreactive cells. The epitopes inducing the strongest responses were not those with the highest HLA binding, suggesting an effective thymic selection in MS patients. Our data extend the concept that the frequency of myelin-reactive T cells in MS patient blood is not increased compared to HC. The description of this set of myelin-derived peptides (MHC class I restricted, recognized by CD8+ T cells) offers new tools to explore the CD8+ cell role in MS.
INSERM U643, et ITERT, Nantes, France.
Laureline
L
Berthelot
David-Axel
DA
Laplaud
Ségolène
S
Pettré
Caroline
C
Ballet
Laure
L
Michel
Sophie
S
Hillion
Cécile
C
Braudeau
Francine
F
Connan
Fabienne
F
Lefrère
Sandrine
S
Wiertlewski
Jean-Gérard
JG
Guillet
Sophie
S
Brouard
Jeannine
J
Choppin
Jean-Paul
JP
Soulillou
D000328:Adult; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism
D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma