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

J Exp Med. 2017 May 1;214(5):1529-1546. doi: 10.1084/jem.20150402. Epub 2017 Apr 20.

Abstract

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.

MeSH terms

  • Cell Differentiation / physiology
  • Chemokine CXCL13 / metabolism
  • Cytokines / physiology*
  • Dendritic Cells / physiology*
  • Humans
  • Inducible T-Cell Co-Stimulator Protein / metabolism
  • Interleukin-21
  • Interleukins / metabolism
  • OX40 Ligand / physiology*
  • Programmed Cell Death 1 Receptor / metabolism
  • Proto-Oncogene Proteins c-bcl-6 / metabolism
  • Receptors, CXCR5 / metabolism
  • Receptors, Immunologic / metabolism
  • Th2 Cells / physiology*
  • Thymic Stromal Lymphopoietin

Substances

  • BCL6 protein, human
  • BTLA protein, human
  • CXCL13 protein, human
  • CXCR5 protein, human
  • Chemokine CXCL13
  • Cytokines
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukins
  • OX40 Ligand
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, CXCR5
  • Receptors, Immunologic
  • Interleukin-21
  • Thymic Stromal Lymphopoietin