Frontiers in Immunology (Jan 2018)

Ex Vivo Expanded Human Non-Cytotoxic CD8+CD45RClow/− Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice

  • Séverine Bézie,
  • Séverine Bézie,
  • Séverine Bézie,
  • Dimitri Meistermann,
  • Dimitri Meistermann,
  • Dimitri Meistermann,
  • Laetitia Boucault,
  • Laetitia Boucault,
  • Laetitia Boucault,
  • Stéphanie Kilens,
  • Stéphanie Kilens,
  • Johanna Zoppi,
  • Johanna Zoppi,
  • Elodie Autrusseau,
  • Elodie Autrusseau,
  • Elodie Autrusseau,
  • Audrey Donnart,
  • Véronique Nerrière-Daguin,
  • Véronique Nerrière-Daguin,
  • Véronique Nerrière-Daguin,
  • Frédérique Bellier-Waast,
  • Eric Charpentier,
  • Franck Duteille,
  • Laurent David,
  • Laurent David,
  • Laurent David,
  • Ignacio Anegon,
  • Ignacio Anegon,
  • Ignacio Anegon,
  • Carole Guillonneau,
  • Carole Guillonneau,
  • Carole Guillonneau

DOI
https://doi.org/10.3389/fimmu.2017.02014
Journal volume & issue
Vol. 8

Abstract

Read online

Both CD4+ and CD8+ Tregs play a critical role in the control of immune responses and immune tolerance; however, our understanding of CD8+ Tregs is limited while they are particularly promising for therapeutic application. We report here existence of highly suppressive human CD8+CD45RClow/− Tregs expressing Foxp3 and producing IFNγ, IL-10, IL-34, and TGFβ to mediate their suppressive activity. We demonstrate that total CD8+CD45RClow/− Tregs can be efficiently expanded in the presence of anti-CD3/28 mAbs, high-dose IL-2 and IL-15 and that such expanded Tregs efficiently delay GVHD and human skin transplantation rejection in immune humanized mice. Robustly expanded CD8+ Tregs displayed a specific gene signature, upregulated cytokines and expansion in the presence of rapamycin greatly improved proliferation and suppression. We show that CD8+CD45RClow/− Tregs are equivalent to canonical CD4+CD25highCD127low/− Tregs for suppression of allogeneic immune responses in vitro. Altogether, our results open new perspectives to tolerogenic strategies in human solid organ transplantation and GVHD.

Keywords