Systems analysis of human T helper17 cell differentiation uncovers distinct time-regulated transcriptional modules
Alessia Capone,
Chiara Naro,
Manuela Bianco,
Marco De Bardi,
Floriane Noël,
Paolo Macchi,
Luca Battistini,
Vassili Soumelis,
Elisabetta Volpe,
Claudio Sette
Affiliations
Alessia Capone
Molecular Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy; Department of Biology and Biotechnology Charles Darwin, Sapienza University, Rome, Italy
Chiara Naro
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; IRCCS Fondazione Policlinico Agostino Gemelli, Rome, Italy
Manuela Bianco
Molecular Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy
Marco De Bardi
Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, Italy
Floriane Noël
Laboratoire d'Immunologie et Histocompatibilité, AP-HP, Hôpital St Louis, Paris, France; HIPI Unit, Inserm U976, Institut de Recherche Saint-Louis, Université de Paris, Paris, France
Paolo Macchi
Laboratory of Molecular and Cellular Neurobiology, Centre for Integrative Biology, University of Trento, Trento, Italy
Luca Battistini
Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, Italy
Vassili Soumelis
Laboratoire d'Immunologie et Histocompatibilité, AP-HP, Hôpital St Louis, Paris, France; HIPI Unit, Inserm U976, Institut de Recherche Saint-Louis, Université de Paris, Paris, France
Elisabetta Volpe
Molecular Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy; Corresponding author
Claudio Sette
Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy; Neuroembriology Unit, IRCCS Santa Lucia Foundation, Rome, Italy; Corresponding author
Summary: T helper (Th) 17 cells protect from infections and are pathogenic in autoimmunity. While human Th17 cell differentiation has been defined, the global and stepwise transcriptional changes accompanying this process remain uncharacterized. Herein, by performing transcriptome analysis of human Th17 cells, we uncovered three time-regulated modules: early, involving exclusively “signaling pathways” genes; late, characterized by response to infections; and persistent, involving effector immune functions. To assign them an inflammatory or regulatory potential, we compared Th17 cells differentiated in presence or absence of interleukin (IL)-1β, respectively. Most inflammatory genes belong to the persistent module, whereas regulatory genes are lately or persistently induced. Among inflammatory genes, we identified the effector molecules IL17A, IL17F, IL26, IL6, interferon (IFN)G, IFNK, LTA, IL1A, platelet-derived growth factor (PDGF) A and the transcriptional regulators homeodomain-only protein homeobox (HOPX) and sex-determining-region-Y-box (SOX)2, whose expression was independently validated. This study provides an integrative representation of the stepwise human Th17 differentiation program and offers new perspectives toward therapeutic targeting of Th17-related autoimmune diseases.
