CD71+VISTA+ erythroid cells promote the development and function of regulatory T cells through TGF-β

  • PLoS Biol. 2018 Dec 14;16(12):e2006649. doi: 10.1371/journal.pbio.2006649.
Shima Shahbaz  1 ,  Najmeh Bozorgmehr  1 ,  Petya Koleva  1 ,  Afshin Namdar  1 ,  Juan Jovel  2 ,  Roy A Fava  3  4 ,  Shokrollah Elahi  1  5
Affiliations
  • 1. Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
  • 2. The Applied Genomics Core, Office of Research, University of Alberta, Edmonton, Canada.
  • 3. Department of Veterans Affairs Medical Center, Research Service, White River Junction, Vermont, United States of America.
  • 4. Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, United States of America.
  • 5. Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
PMID: 30550561 DOI: 10.1371/journal.pbio.2006649
Abstract

Cell-surface Transferrin Receptor (CD71+) erythroid cells are abundant in newborns with immunomodulatory properties. Here, we show that neonatal CD71+ erythroid cells express significant levels of V-domain Immunoglobulin (Ig) Suppressor of T Cell Activation (VISTA) and, via constitutive production of transforming growth factor (TGF)- β, play a pivotal role in promotion of naïve CD4+ T cells into regulatory T cells (Tregs). Interestingly, we discovered that CD71+VISTA+ erythroid cells produce significantly higher levels of TGF-β compared to CD71+VISTA- erythroid cells and CD71+ erythroid cells from the VISTA knock-out (KO) mice. As a result, CD71+VISTA+ erythroid cells-compared to CD71+VISTA- and CD71+ erythroid cells from the VISTA KO mice-significantly exceed promotion of naïve CD4+ T cells into induced Tregs (iTreg) via TGF-β in vitro. However, depletion of CD71+ erythroid cells had no significant effects on the frequency of Tregs in vivo. Surprisingly, we observed that the remaining and/or newly generated CD71+ erythroid cells following anti-CD71 antibody administration exhibit a different gene expression profile, evidenced by the up-regulation of VISTA, TGF-β1, TGF-β2, and program death ligand-1 (PDL-1), which may account as a compensatory mechanism for the maintenance of Treg population. We also observed that iTreg development by CD71+ erythroid cells is mediated through the inhibition of key signaling molecules phosphorylated protein kinase B (phospho-Akt) and phosphorylated mechanistic target of rapamycin (phospho-mTOR). Finally, we found that elimination of Tregs using forkhead box P3 (FOXP3)-diptheria toxin receptor (DTR) mice resulted in a significant expansion in the frequency of CD71+ erythroid cells in vivo. Collectively, these studies provide a novel, to our knowledge, insight into the cross-talk between CD71+ erythroid cells and Tregs in newborns. Our results highlight the biological role of CD71+ erythroid cells in the neonatal period and possibly beyond.

Products