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.
Clément Jacquemin  1 ,  Nathalie Schmitt  2 ,  Cécile Contin-Bordes  3 ,  Yang Liu  2 ,  Priya Narayanan  2 ,  Julien Seneschal  3 ,  Typhanie Maurouard  2 ,  David Dougall  2 ,  Emily Spence Davizon  2 ,  Hélène Dumortier  4 ,  Isabelle Douchet  5 ,  Loïc Raffray  6 ,  Christophe Richez  3 ,  Estibaliz Lazaro  3 ,  Pierre Duffau  3 ,  Marie-Elise Truchetet  3 ,  Liliane Khoryati  1 ,  Patrick Mercié  7 ,  Lionel Couzi  7 ,  Pierre Merville  3 ,  Thierry Schaeverbeke  7 ,  Jean-François Viallard  7 ,  Jean-Luc Pellegrin  7 ,  Jean-François Moreau  3 ,  Sylviane Muller  8 ,  Sandy Zurawski  2 ,  Robert L Coffman  9 ,  Virginia Pascual  2 ,  Hideki Ueno  10 ,  Patrick Blanco  11
Affiliations
  • 1. University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France.
  • 2. Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
  • 3. University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
  • 4. CNRS, Immunopathology and therapeutic chemistry/Laboratory of excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire;University of Strasbourg, F-67081 Strasbourg, France.
  • 5. CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France.
  • 6. CHU de Bordeaux, F-33076 Bordeaux, France.
  • 7. University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CHU de Bordeaux, F-33076 Bordeaux, France.
  • 8. CNRS, Immunopathology and therapeutic chemistry/Laboratory of excellence MEDALIS, Institut de Biologie Moléculaire et Cellulaire;University of Strasbourg, F-67081 Strasbourg, France; University of Strasbourg Institute for Advanced Study, F-67081 Strasbourg, France.
  • 9. Dynavax Technologies Corporation, Berkeley, CA 94710, USA.
  • 10. Baylor Institute for Immunology Research, Dallas, TX 75204, USA. Electronic address: [email protected].
  • 11. University Bordeaux, CIRID, UMR/CNRS 5164, F-33000 Bordeaux, France; CNRS, CIRID, UMR 5164, F-33000 Bordeaux, France; Baylor Institute for Immunology Research, Dallas, TX 75204, USA; CHU de Bordeaux, F-33076 Bordeaux, France. Electronic address: [email protected].
PMID: 26070486 DOI: 10.1016/j.immuni.2015.05.012
Abstract

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.