Induction of CD4 + CD25 + Foxp3 + regulatory T cells by mesenchymal stem cells is associated with RUNX complex factors

Immunol Res. 2018 Feb;66(1):207-218. doi: 10.1007/s12026-017-8973-4.

Abstract

Among the particular immunomodulation properties of mesenchymal stem cells (MSCs), one relies on their capacity to regulatory T cell (Treg) induction from effector T cells. Stable expression of Foxp3 has a dominant role in suppressive phenotype and stability of induced regulatory T cells (iTregs). How MSCs induce stable Foxp3 expression in iTregs remains unknown. We previously showed MSCs could enhance demethylation of Treg-specific demethylated region (TSDR) in iTregs in cell-cell contact manner (unpublished data). Here, we evaluated the possible effect of MSCs on the mRNA expression of Runx complex genes (Runx1, Runx3, and CBFB) that perch on TSDR in iTregs and play the main role in suppressive properties of Tregs, a regulatory pathway that has not yet been explored by MSCs. Also, we investigated the mRNA expression of MBD2 that promotes TSDR demethylation in Tregs. We first showed that in vitro MSC-iTreg induction was associated with strong mRNA modifications of genes involved in Runx complex. We next injected high doses of MSCs in a murine model of C57BL/6 into Balb/C allogeneic skin transplantation to prolong allograft survival. When splenocytes of grafted mice were analyzed, we realized that the Foxp3 expression was increased at day 5 and 10 post-graft merely in MSC-treated mice. Furthermore, Foxp3 mRNA expression was associated with modified Runx complex mRNA expression comparable to what was shown in in vitro studies. Hence, our data identify a possible mechanism in which MSCs convert conventional T cells to iTreg through strong modifications of mRNA of genes that are involved in Runx complex of Foxp3.

Keywords: Demethylation; Mesenchymal stem cells; Regulatory T cells; Runx complex.

MeSH terms

  • Animals
  • CD4 Antigens / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Core Binding Factor alpha Subunits / genetics
  • Core Binding Factor alpha Subunits / metabolism*
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymphocyte Activation
  • Mesenchymal Stem Cells / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics*
  • Skin Transplantation
  • T-Lymphocytes, Regulatory / immunology*
  • Transplantation, Homologous

Substances

  • CD4 Antigens
  • Core Binding Factor alpha Subunits
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Mbd2 protein, mouse
  • RNA, Messenger