title: T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis.
abstract: Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by persistent inflammation orchestrated by cluster of differentiation (CD) 4 T helper (Th) cells. In particular, Th1 and Th17 cells amplify, whereas T regulatory (Treg) cells moderate inflammation. The role of other Th subsets in MS is not clear. In the present study, we investigated the generation of different Th responses by human dendritic cells (DCs) in MS. We compared the production of several Th cytokines by naive CD4+ T-cells polarized with myeloid and plasmacytoid DCs (mDCs and pDCs) in healthy donors (HD) and relapsing-remitting (RR)-MS patients. We found that resiquimod-stimulated mDCs were able to activate Th17 differentiation, whereas pDCs induced interleukin (IL)-10-producing Th cells. Surprisingly, resiquimod-stimulated pDCs from MS patients also significantly induced the differentiation of Th9 cells, which produce IL-9 and are known to be involved in allergic diseases. We investigated the potential role of IL-9 in MS. We found that IL-9 activated signal transducer and activator of transcription (STAT) 1 and STAT5 phosphorylation and interfered with IL-17 and interferon (IFN) regulatory transcription factor (IRF)-4 expression in Th17-polarized cells. Moreover, in the cerebrospinal fluid (CSF) of 107 RR-MS patients, IL-9 inversely correlated with indexes of inflammatory activity, neurodegeneration and disability progression of MS. High levels of IL-9 were associated with the absence of IL-17 in the CSF of RR-MS patients. Our results demonstrate a Th9-inducing potential of pDCs in MS, suggesting an immunoregulatory role leading to attenuation of the exaggerated Th17 inflammatory response.
authors.affiliation: *Neuroimmunology Unit, Santa Lucia Foundation, Rome 00143, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ruocco
authors.affiliation: †Dipartimento di Medicina dei Sistemi, University Tor Vergata, Rome 00133, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.affiliation: †Dipartimento di Medicina dei Sistemi, University Tor Vergata, Rome 00133, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.affiliation: †Dipartimento di Medicina dei Sistemi, University Tor Vergata, Rome 00133, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Macchiarulo
authors.affiliation: †Dipartimento di Medicina dei Sistemi, University Tor Vergata, Rome 00133, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Barbieri
authors.affiliation: *Neuroimmunology Unit, Santa Lucia Foundation, Rome 00143, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: De Bardi
authors.affiliation: *Neuroimmunology Unit, Santa Lucia Foundation, Rome 00143, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Borsellino
authors.affiliation: ‡Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Finardi
authors.affiliation: §Multiple Sclerosis Centre, Santa Lucia Foundation, Rome 00179, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Grasso
authors.affiliation: ║Department of Neuroscience "Lancisi", San Camillo Hospital, Rome 00151, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ruggieri
authors.affiliation: ║Department of Neuroscience "Lancisi", San Camillo Hospital, Rome 00151, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Gasperini
authors.affiliation: ‡Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.affiliation: †Dipartimento di Medicina dei Sistemi, University Tor Vergata, Rome 00133, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.affiliation: *Neuroimmunology Unit, Santa Lucia Foundation, Rome 00143, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.affiliation: *Neuroimmunology Unit, Santa Lucia Foundation, Rome 00143, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Volpe
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002450:Cell Communication; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D016906:Interleukin-9 / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D041623:Tomography, Optical Coherence; D000099218:Interferon Regulatory Factor-4
chemical_list: D007093:Imidazoles; D018836:Inflammation Mediators; D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D016906:Interleukin-9; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D000099218:Interferon Regulatory Factor-4; C508607:IL9 protein, human; C494079:STAT1 protein, human; C402365:resiquimod