Generation of human regulatory T cells de novo with suppressive function prevent xenogeneic graft versus host disease

Xiaofeng Qian, Ke Wang, Xuehao Wang, Song Guo Zheng, Ling Lu

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Treatment with rapamycin (RAPA) favorably affects regulatory T cells (Treg) in vivo, and RAPA induces the de novo expression of FOXP3 in murine alloantigen-specific T cells. Whether RAPA acts independently or with transforming growth factor beta (TGF-β) to produce ex vivo-induced Treg generation is unknown. Naïve CD4+ T cells isolated from peripheral blood mononuclear cells were stimulated with anti-CD3/CD28 coated beads in the presence of IL-2 for 5 to 7 days. Ten ng/ml of TGF-β (1 to 100 ng/mL RAPA) was added to some of the cultures. The phenotypes were analyzed with flow cytometry. The conditioned cells were cocultured with CFSE-labeled T cells in different ratios for 5 days. CFSE dilution indicating T response cell proliferation was analyzed by flow cytometry. Xenogeneic graft-versus-host disease (x-GVHD) was induced by transplanting human peripheral blood mononuclear cells into RAG2-/- γc-/- mice exposed to total body irradiation, and various factors in the subjects were subsequently compared. CD4 cells induced by rapamycin and TGF-β (CD4RAPA/TGF-β) expressed the natural Treg phenotypes and trafficking receptors, and no significant cytotoxicity was observed. CD4RAPA/TGF-β was anergic and demonstrated potent suppressive activity in vitro. Although the transfer of human peripheral blood mononuclear cells into RAG2-/- γc -/- mice caused x-GVHD, the cotransfer of CD4 RAPA/TGF-β decreased human cell engraftment and extended survival in mice. RAPA plus TGF-β induces human naïve T cells to become suppressor cells, a novel strategy for treating human autoimmune diseases and preventing allograft rejection.

Original languageEnglish (US)
Pages (from-to)630-637
Number of pages8
JournalInternational Immunopharmacology
Volume11
Issue number5
DOIs
StatePublished - May 2011

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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