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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:140

Article

Paroni, Moira¹  Maltese, Virginia^2,3  De Simone, Marco¹  Ranzani, Valeria¹  Larghi, Paola¹  Fenoglio, Chiara^2,3  Pietroboni, Anna M.^2,3  De Riz, Milena A.^2,3  Crosti, Maria C.¹  Maglie, Stefano¹  Moro, Monica¹  Caprioli, Flavio^4,7  Rossi, Riccardo¹  Rossetti, Grazisa¹  Galimberti, Daniela^2,3  Pagani, Massimiliano^1,5  Scarpini, Elio^2,3  Abrignani, Sergio^1,6  Geginat, Jens¹ 

[1] Ist Nazl Genet Mol Romeo & Enrica Invernizzi, INGM, Milan, Italy

[2] Univ Milan, Dept Pathophysiol & Transplantat, Neurol Unit, Milan, Italy

[3] IRCCS Osped Policlin, Fdn Ca Granda, Milan, Italy

[4] Univ Milan, Dept Pathophysiol & Transplantat, Milan, Italy

[5] Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy

[6] Univ Milan, DISCCO, Dept Clin Sci & Community Hlth, Milan, Italy

[7] IRCCS Osped Policlin, Fdn Ca Granda, Gastroenterol & Endoscopy Unit, Milan, Italy

关键词: T(H)1/T(H)17 central memory T cells;    autoreactivity;    multiple sclerosis;    John Cunningham Virus;    natalizumab;    fingolimod;   

DOI  :  10.1016/j.jaci.2016.11.045

来源: Elsevier

【 摘 要 】

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: T(H)1/T(H)17 central memory (T(H)1/T(H)17(CM)) cells were selectively increased in peripheral blood of patients with relapsing-remitting MS with a high disease score. T(H)1/T(H)17(CM) cells were closely related to conventional T(H)17 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 T(H)1/T(H)17 subsets. However, while T(H)1 cells responded consistently to viruses, T(H)1/T(H)17(CM) cells 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 T(H)1/T(H)17(CM) cells but also blocked virus-specific T(H)1 cells. Conclusions: We propose that autoreactive T(H)1/T(H)17(CM) cells expand in patients with MS and promote relapses after bystander recruitment to the CNS, whereas T(H)1 cells perform immune surveillance. Thus the selective targeting of T(H)1/T(H)17 cells could inhibit relapses without causing John Cunningham virus-dependent progressive multifocal encephalomyelitis.

【 授权许可】

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