Blood Journal
Leading the way in experimental and clinical research in hematology

Cell autonomous role of TGFβ and IL-2 receptor in CD4+ and CD8+ inducible regulatory T cell generation during graft-versus-host disease

  1. Norifumi Sawamukai1,
  2. Atsushi Satake1,
  3. Amanda M. Schmidt1,
  4. Ian T. Lamborn1,
  5. Priti Ojha1,
  6. Yoshiya Tanaka2, and
  7. Taku Kambayashi1,*
  1. 1 Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States;
  2. 2 First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
  1. * Corresponding author; email: taku.kambayashi{at}uphs.upenn.edu

Abstract

FoxP3+ regulatory T cells (Tregs) suppress graft-versus-host disease (GVHD) while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from expansion of pre-existing natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplant recipient. In an MHC-mismatched model of acute GVHD, we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wildtype and FoxP3-deficient mice suggested that both pre-existing donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8+FoxP3+ T cells represented ~70% of the iTreg pool. These CD8+FoxP3+ T cells shared phenotypic markers with their CD4+ counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4+ and CD8+ Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex make up of the donor-derived FoxP3+ Treg pool in allogeneic recipients and their potential role in protection against GVHD.

  • Submitted July 18, 2011.
  • Accepted March 31, 2012.