Elodie Rivière1, Juliette Pascaud2, Alexandre Virone2, Anastasia Dupré2, Bineta Ly2, Audrey Paoletti2, Raphaèle Seror2, Nicolas Tchitchek2, Michael Mingueneau3, Nikaïa Smith4, Darragh Duffy4, Lydie Cassard5, Nathalie Chaput5, Sabrina Pengam6, Vanessa Gauttier6, Nicolas Poirier6, Xavier Mariette2, Gaetane Nocturne2. 1. Université Paris-Saclay, INSERM, CEA, Centre de Recherche en Immunologie des Infections Virales et des Maladies Auto-Immunes, Hôpital Bicêtre, AP-HP, Recherche et Développement, Arthritis Fondation Courtin, Paris, France. 2. Université Paris-Saclay, INSERM, CEA, Centre de Recherche en Immunologie des Infections Virales et des Maladies Auto-Immunes, Hôpital Bicêtre, AP-HP, Paris, France. 3. Biogen, Cambridge, Massachusetts. 4. Laboratoire d'Immunobiologie des Cellules Dendritiques, INSERM U1223, Institut Pasteur, Paris, France. 5. Université Paris-Saclay, Institut Gustave Roussy, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Laboratoire d'Immunomonitoring en Oncologie, INSERM, CNRS, Paris, France. 6. OSE Immunotherapeutics, Nantes, France.
Abstract
OBJECTIVE: Primary Sjögren's syndrome (SS) is characterized by a lymphocytic infiltration of salivary glands (SGs) and the presence of an interferon (IFN) signature. SG epithelial cells (SGECs) play an active role in primary SS pathophysiology. We undertook this study to examine the interactions between SGECs and T cells in primary SS and the role of the interleukin-7 (IL-7)/IFN axis. METHODS: Primary cultured SGECs from control subjects and patients with primary SS were stimulated with poly(I-C), IFNα, or IFNγ. T cells were sorted from blood and stimulated with IL-7. CD25 expression was assessed by flow cytometry. SG explants were cultured for 4 days with anti-IL-7 receptor (IL-7R) antagonist antibody (OSE-127), and transcriptomic analysis was performed using the NanoString platform. RESULTS: Serum IL-7 level was increased in patients with primary SS compared to controls and was associated with B cell biomarkers. IL7R expression was decreased in T cells from patients with primary SS compared to controls. SGECs stimulated with poly(I-C), IFNα, or IFNγ secreted IL-7. IL-7 stimulation increased the activation of T cells, as well as IFNγ secretion. Transcriptomic analysis of SG explants showed a correlation between IL7 and IFN expression. Finally, explants cultured with anti-IL-7R antibody showed decreased IFN-stimulated gene expression. CONCLUSION: These results suggest the presence of an IL-7/IFNγ amplification loop involving SGECs and T cells in primary SS. IL-7 was secreted by SGECs stimulated with type I or type II IFN and, in turn, activated T cells that secrete type II IFN. An anti-IL-7R antibody decreased the IFN signature in T cells in primary SS and could be of therapeutic interest.
OBJECTIVE: Primary Sjögren's syndrome (SS) is characterized by a lymphocytic infiltration of salivary glands (SGs) and the presence of an interferon (IFN) signature. SG epithelial cells (SGECs) play an active role in primary SS pathophysiology. We undertook this study to examine the interactions between SGECs and T cells in primary SS and the role of the interleukin-7 (IL-7)/IFN axis. METHODS: Primary cultured SGECs from control subjects and patients with primary SS were stimulated with poly(I-C), IFNα, or IFNγ. T cells were sorted from blood and stimulated with IL-7. CD25 expression was assessed by flow cytometry. SG explants were cultured for 4 days with anti-IL-7 receptor (IL-7R) antagonist antibody (OSE-127), and transcriptomic analysis was performed using the NanoString platform. RESULTS: Serum IL-7 level was increased in patients with primary SS compared to controls and was associated with B cell biomarkers. IL7R expression was decreased in T cells from patients with primary SS compared to controls. SGECs stimulated with poly(I-C), IFNα, or IFNγ secreted IL-7. IL-7 stimulation increased the activation of T cells, as well as IFNγ secretion. Transcriptomic analysis of SG explants showed a correlation between IL7 and IFN expression. Finally, explants cultured with anti-IL-7R antibody showed decreased IFN-stimulated gene expression. CONCLUSION: These results suggest the presence of an IL-7/IFNγ amplification loop involving SGECs and T cells in primary SS. IL-7 was secreted by SGECs stimulated with type I or type II IFN and, in turn, activated T cells that secrete type II IFN. An anti-IL-7R antibody decreased the IFN signature in T cells in primary SS and could be of therapeutic interest.
Authors: Gwenny M Verstappen; Lu Gao; Sarah Pringle; Erlin A Haacke; Bert van der Vegt; Silvia C Liefers; Vishal Patel; Yanhua Hu; Sumanta Mukherjee; Julie Carman; Laurence C Menard; Frederik K L Spijkervet; Arjan Vissink; Hendrika Bootsma; Frans G M Kroese Journal: Front Immunol Date: 2021-07-06 Impact factor: 7.561