title: Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.
abstract: BACKGROUND
  Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is caused by autoreactive T cells and associated with viral infections. However, the phenotype of pathogenic T cells in peripheral blood remains to be defined, and how viruses promote MS is debated.
  
  
  OBJECTIVE
  We aimed to identify and characterize potentially pathogenic autoreactive T cells, as well as protective antiviral T cells, in patients with MS.
  
  
  METHODS
  We analyzed CD4+helper T-cell subsets from peripheral blood or cerebrospinal fluid for cytokine production, gene expression, plasticity, homing potentials, and their reactivity to self-antigens and viral antigens in healthy subjects and patients with MS. Moreover, we monitored their frequencies in untreated and fingolimod- or natalizumab-treated patients with MS.
  
  
  RESULTS
  TH1/TH17 central memory (TH1/TH17CM) cells were selectively increased in peripheral blood of patients with relapsing-remitting MS with a high disease score. TH1/TH17CMcells were closely related to conventional TH17 cells but had more pathogenic features. In particular, they could shuttle between lymph nodes and the CNS and produced encephalitogenic cytokines. The cerebrospinal fluid of patients with active MS was enriched for CXCL10 and contained mainly CXCR3-expressing TH1 and TH1/TH17 subsets. However, while TH1 cells responded consistently to viruses, TH1/TH17CMcells reacted strongly with John Cunningham virus in healthy subjects but responded instead to myelin-derived self-antigens in patients with MS. Fingolimod and natalizumab therapies efficiently targeted autoreactive TH1/TH17CMcells but also blocked virus-specific TH1 cells.
  
  
  CONCLUSIONS
  We propose that autoreactive TH1/TH17CMcells expand in patients with MS and promote relapses after bystander recruitment to the CNS, whereas TH1 cells perform immune surveillance. Thus the selective targeting of TH1/TH17 cells could inhibit relapses without causing John Cunningham virus-dependent progressive multifocal encephalomyelitis.
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Moira
authors.initials: M
authors.lastname: Paroni
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan and Fondazione Cá Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Maltese
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Simone
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ranzani
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Larghi
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan and Fondazione Cá Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan and Fondazione Cá Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Pietroboni
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan and Fondazione Cá Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Milena A
authors.initials: MA
authors.lastname: De Riz
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Crosti
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Maglie
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Moro
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Gastroenterology and Endoscopy Unit, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Caprioli
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rossi
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Grazisa
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan and Fondazione Cá Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Pagani
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan and Fondazione Cá Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy; DISCCO, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy. Electronic address: geginat@ingm.org.
authors.forename: Jens
authors.initials: J
authors.lastname: Geginat
mesh_terms: D000328:Adult; D000956:Antigens, Viral / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D016207:Cytokines / Q000134:cerebrospinal fluid / Q000276:immunology; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007577:JC Virus / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D000069442:Natalizumab / Q000627:therapeutic use; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D001324:Autoantigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D000069442:Natalizumab; D000068876:Fingolimod Hydrochloride
keywords: John Cunningham Virus; T(H)1/T(H)17 central memory T cells; autoreactivity; fingolimod; multiple sclerosis; natalizumab