OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response

Immunity. 2015 Jun 16;42(6):1159-70. doi: 10.1016/j.immuni.2015.05.012. Epub 2015 Jun 9.


Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS(+) blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4(+) T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antigen Presentation
  • B-Lymphocytes / immunology
  • Cell Differentiation
  • Cells, Cultured
  • Cytokines / metabolism
  • Disease Progression
  • Female
  • Humans
  • Immunologic Memory
  • Inducible T-Cell Co-Stimulator Protein / metabolism
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Myeloid Cells / immunology*
  • OX40 Ligand / metabolism*
  • RNA / immunology
  • Receptors, OX40 / metabolism*
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Toll-Like Receptor 7 / metabolism
  • Young Adult


  • Cytokines
  • ICOS protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • OX40 Ligand
  • Receptors, OX40
  • TNFRSF4 protein, human
  • Toll-Like Receptor 7
  • RNA