TSLP-activated dendritic cells induce human T follicular helper cell differentiation through OX40-ligand

• DOI: 10.1084/jem.20150402
• Publication Date: 2017-04-20T14:10:13Z
• Authors: Lucia Pattarini; Coline Trichot; Sofia Bogiatzi; Maximilien Grandc...; Stephan Meller; Zela Keuylian; Melanie Durand; Elisabetta Volpe; Stefania Madonna; Andrea Cavani; Andrea Chiricozzi; Marco Romanelli; Toshiyuki Hori; Alain Hovnanian; Bernhard Homey; Vassili Soumelis
• Keywords: Receptors, CXCR5; Interleukins; Programmed Cell Death 1 Receptor; Cell Differentiation; OX40 Ligand; Dendritic Cells; Chemokine CXCL13; Cell Differentiation; Chemokine CXCL13; Cytokines; Dendritic Cells; Humans; Inducible T-Cell Co-Stimulator Protein; Interleukins; OX40 Ligand; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins c-bcl-6; Receptors, CXCR5; Receptors, Immunologic; Th2 Cells; Immunology and Allergy; Immunology; Inducible T-Cell Co-Stimulator Protein; 03 medical and health sciences; Th2 Cells; 0302 clinical medicine; Thymic Stromal Lymphopoietin; Proto-Oncogene Proteins c-bcl-6; Cytokines; Humans; Receptors, Immunologic; Research Articles

T follicular helper cells (Tfh) are important regulators of humoral responses. Human Tfh polarization pathways have been thus far associated with Th1 and Th17 polarization pathways. How human Tfh cells differentiate in Th2-skewed environments is unknown. We show that thymic stromal lymphopoietin (TSLP)–activated dendritic cells (DCs) promote human Tfh differentiation from naive CD4 T cells. We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells. TSLP-induced T cells expressed CXCR5, CXCL13, ICOS, PD1, BCL6, BTLA, and SAP, among other Tfh markers. Functionally, TSLP-DC–polarized T cells induced IgE secretion by memory B cells, and this depended on IL-4Rα. TSLP-activated DCs stimulated circulating memory Tfh cells to produce IL-21 and CXCL13. Mechanistically, TSLP-induced Tfh differentiation depended on OX40-ligand, but not on ICOS-ligand. Our results delineate a pathway of human Tfh differentiation in Th2 environments.