title: Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjögren's syndrome.
abstract: Follicular helper T cells (Tfh), which play a pivotal role in B cell activation and differentiation in lymphoid structures, secrete IL-21 whose augmented secretion is a hallmark of several autoimmune diseases. To decipher the cellular and molecular interactions occurring in salivary glands of patients suffering from primary Sjögren's syndrome (pSS), we investigated whether salivary gland epithelial cells (SGECs) were capable to induce Tfh differentiation. Co-cultures of naïve CD4(+) T cells and SGECs from both patients with pSS and controls were performed. Here, we report that IL-6 and ICOSL expression by SGECs contributes to naïve CD4(+) T differentiation into Tfh cells, as evidenced by their acquisition of a specific phenotype, characterized by Bcl-6, ICOS and CXCR5 expression and IL-21 secretion, but also but by their main functional feature: the capacity to enhance B lymphocytes survival. We demonstrated an increase of serum IL-21 with systemic activity. Finally, we analyzed the potential occurrence of a genetic association between IL-21 or IL-21R gene polymorphisms and pSS or elevated IL-21 secretion. This study, which demonstrates a direct induction of Tfh differentiation by SGECs, emphasizes a yet unknown pathogenic role of SGECs and suggests that Tfh and IL-21 might be relevant biomarkers and/or therapeutic targets in primary Sjögren's syndrome.
authors.affiliation: Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France; Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Ya-Zhuo
authors.initials: YZ
authors.lastname: Gong
authors.affiliation: University of California San Francisco, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, 374 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Nititham
authors.affiliation: University of California San Francisco, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, 374 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Corinne Miceli-Richard, Xavier Mariette: Université Paris-Sud 11, Rhumatologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Miceli-Richard
authors.affiliation: Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France; Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Sordet
authors.affiliation: Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France; Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Wachsmann
authors.affiliation: Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France; Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Siamak
authors.initials: S
authors.lastname: Bahram
authors.affiliation: Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France; Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Georgel
authors.affiliation: University of California San Francisco, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, 374 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France; Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Sibilia
authors.affiliation: Corinne Miceli-Richard, Xavier Mariette: Université Paris-Sud 11, Rhumatologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
authors.affiliation: Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France; Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Ghada
authors.initials: G
authors.lastname: Alsaleh
authors.affiliation: Immunorhumatologie moléculaire, INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France; Service de Rhumatologie, Centre National de Référence pour les Maladies Systémiques Autoimmunes Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. Electronic address: jacques-eric.gottenberg@chru-strasbourg.fr.
authors.forename: Jacques-Eric
authors.initials: JE
authors.lastname: Gottenberg
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000378:metabolism*; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D007378:Interleukins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D053655:Receptors, Interleukin-21 / Q000235:genetics; D012469:Salivary Glands / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D015850:Interleukin-6; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21
keywords: Epithelial cells; Follicular helper T cells; Germinal centers; IL-21; Sjögren's syndrome