Enhancement of Graft-Versus-Host Disease Control Efficacy by Adoptive Transfer of Type 1 Regulatory T Cells in Bone Marrow Transplant Model

Interleukin (IL)-10-producing type 1 regulatory T (Tr1) cells, which are Foxp3(-)memory T lymphocytes, play important roles in peripheral immune tolerance. We investigated whether Tr1 cells exert immunoregulatory effects in a mouse model of acute graft-versus-host disease (GVHD). Mouse CD4(+) T cells were induced to differentiate in vitro into Tr1 cells using vitamin D3 and dexamethasone, and these donor-derived Tr1 cells were infused on the day of bone marrow transplantation. The Tr1 cell-transferred group showed less weight-loss and a twofold higher survival rate than the GVHD group, together with markedly decreased histopathologic grades. It was associated with the expansion of CD4(+)IL-4(+) type 2 T-helper (Th2) cells and CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells. Furthermore, Tr1 cells decreased the numbers of CD4(+)interferon-gamma(+) Th1 and CD4(+)IL-17(+) Th17 cells. Recipient mice harbored some Foxp3(+) Tregs due to adoptive transfer of Tr1 cells, together with the upregulated expression of costimulatory molecules, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and inducible T-cell costimulator (ICOS); however, the Treg cells did not show the plasticity. Therefore, adoptive Tr1 cell therapy may be effective against manifestations of GVHD, exert immunomodulatory effects in a manner dependent on CTLA-4 and ICOS, and induce differentiation of the transferred Tr1 cells into Foxp3(+) Treg cells.