title: Increased CD8+ T cell responses to apoptotic T cell-associated antigens in multiple sclerosis.
abstract: BACKGROUND
  Here, we evaluated the hypothesis that CD8+ T cell responses to caspase-cleaved antigens derived from effector T cells undergoing apoptosis, may contribute to multiple sclerosis (MS) immunopathology.
  
  
  METHODS
  The percentage of autoreactive CD8+ T effector cells specific for various apoptotic T cell-associated self-epitopes (apoptotic epitopes) were detected in the peripheral blood and cerebrospinal fluid (CSF) by both enzyme-linked immunospot and dextramers of class I molecules complexed with relevant apoptotic epitopes. Moreover, the capacity of dextramer+ CD8+ T cells to produce interferon (IFN)-γ and/or interleukin (IL)-17 in response to the relevant apoptotic epitopes was evaluated by the intracellular cytokine staining. Cross-presentation assay of apoptotic T cells by dendritic cells was also evaluated ex vivo.
  
  
  RESULTS
  We found that polyfunctional (IFN-γ and/or IL-17 producing) autoreactive CD8+ T cells specific for apoptotic epitopes were represented in MS patients with frequencies significantly higher than in healthy donors. These autoreactive CD8+ T cells with a strong potential to produce IFN-γ or IL-17 in response to the relevant apoptotic epitopes were significantly accumulated in the CSF from the same patients. In addition, the frequencies of these autoreactive CD8+ T cells correlated with the disease disability. Cross-presentation assay revealed that caspase-cleaved cellular proteins are required to activate apoptotic epitope-specific CD8+ T cells ex vivo.
  
  
  CONCLUSIONS
  Taken together, these data indicate that apoptotic epitope-specific CD8+ T cells with strong inflammatory potential are recruited at the level of the inflammatory site, where they may be involved in MS immunopathology through the production of high levels of inflammatory cytokines.
authors.affiliation: Dipartimento di Scienze Biomediche, Sperimentali e Cliniche and Neurofarba, Università of Firenze, Azienda Ospedaliera di Careggi, Largo Brambilla 6, 50134 Firenze, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lolli
authors.forename: Helene
authors.initials: H
authors.lastname: Martini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Citro
authors.forename: Debora
authors.initials: D
authors.lastname: Franceschini
authors.forename: Emilio
authors.initials: E
authors.lastname: Portaccio
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Amato
authors.forename: Rosella
authors.initials: R
authors.lastname: Mechelli
authors.forename: Viviana
authors.initials: V
authors.lastname: Annibali
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Marco
authors.initials: M
authors.lastname: Salvetti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Barnaba
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000941:Antigens / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004185:Disability Evaluation; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007371:Interferon-gamma / Q000494:pharmacology; D020381:Interleukin-17 / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D016207:Cytokines; D000939:Epitopes; D007202:Indicators and Reagents; D020381:Interleukin-17; D007371:Interferon-gamma; D020169:Caspases
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