Donor bone marrow cells are essential for iNKT cell-mediated Foxp3+ Treg cell expansion in a murine model of transplantation tolerance

Eur J Immunol. 2017 Apr;47(4):734-742. doi: 10.1002/eji.201646670. Epub 2017 Mar 21.

Abstract

Mixed chimerism induction is the most reliable method for establishing transplantation tolerance. We previously described a novel treatment using a suboptimal dose of anti-CD40 ligand (anti-CD40L) and liposomal formulation of a ligand for invariant natural killer T cells administered to sub-lethally irradiated recipient mice after donor bone marrow cell (BMC) transfer. Recipient mice treated with this regimen showed expansion of a Foxp3-positive regulatory T(Treg) cell phenotype, and formation of mixed chimera. However, the mechanism of expansion and bioactivity of Treg cells remains unclear. Here, we examine the role of donor BMCs in the expansion of bioactive Treg cells. The mouse model was transplanted with a heart allograft the day after treatment. The results showed that transfer of spleen cells in place of BMCs failed to deplete host interferon (IFN)-γ-producing CD8+ T cells, expand host Ki67+ CD4+ CD25+ Foxp3+ Treg cells, and prolong graft survival. Severe combined immunodeficiency mice who received Treg cells obtained from BMC-recipients accepted skin grafts in an allo-specific manner. Myeloid-derived suppressor cells, which were a copious cell subset in BMCs, enhanced the Ki67 expression of Treg cells. This suggests that donor BMCs are indispensable for the expansion of host bioactive Treg cells in our novel treatment for transplant tolerance induction.

Keywords: Bone marrow · NKT cells · Regulatory T cells · Tolerance · Transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / immunology*
  • Bone Marrow Transplantation*
  • Forkhead Transcription Factors / metabolism
  • Graft Rejection / immunology*
  • Graft Survival
  • Heart Transplantation*
  • Humans
  • Isoantigens / immunology
  • Ki-67 Antigen / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, SCID
  • Models, Animal
  • Myeloid-Derived Suppressor Cells / immunology*
  • Natural Killer T-Cells / immunology*
  • Skin Transplantation*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / transplantation
  • Tissue Donors
  • Transplantation Chimera
  • Transplantation Tolerance*

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Isoantigens
  • Ki-67 Antigen