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

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.

Chimerism through the activation of invariant natural killer T cells prolongs graft survival after transplantation of induced pluripotent stem cell–derived allogeneic cardiomyocytes

“…The expansion of Tregs and donor-derived dendritic cells in the recipient thymus was accompanied by a sequential clonal deletion in the donor-reactive CD8 + T cells secreting IFN-g, which led to the engraftment of donor bone marrow cells [ 13 ]. The transplantation of donor splenocytes instead of bone marrow cells fails to expand Tregs, depletes donor-reactive CD8 + T cells, and prolong graft survival [ 29 ]. This indicates that donor bone marrow cells are required for further expansion of Tregs and are indispensable for the establishment of mixed-chimera mice.…”

Classic and Current Opinions in Human Organ and Tissue Transplantation

“…NK cells are also equipped with stimulatory receptors activated by antigens on non-self-cells. NK cells also assist CD28+ host T lymphocytes and encourage allograft rejection [91]. NK cells have been identified to play an active role in chronic and acute rejection of solid organ grafts [92].…”

The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator?

“…MDSCs are also an abundant cell subset during bone marrow cell (BMC) transfer. MDSCs are essential for iNKT cells-mediated Foxp3+ Treg cell expansion in recipient mice of transplantation tolerance [ 135 ]. NKT cells act through bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases [ 136 ].…”