An instructive role of donor macrophages in mixed chimeras in the induction of recipient CD4(+)Foxp3(+) Treg cells.

The immune regulatory function of macrophages (Møs) in mixed chimeras has not been determined. In the present study, with a multi-lineage B6-to-BALB/c mixed chimeric model, we examined the ability of donor-derived splenic Møs in the induction of regulatory T cells (Treg). B6 splenic Møs from mixed chimeras induced significantly less cell proliferation, more IL-10 and TGF-β, and less IL-2 and IFN-γ productions of CD4(+) T cells from BALB/c mice than naive B6 Møs did, whereas they showed similar stimulatory activity to the third part C3H CD4(+) T cells. Importantly, highly purified donor F4/80(+)CD11c(-) Møs efficiently induced recipient CD4(+)Foxp3(+) Treg cells from CD4(+)CD25(-)Foxp3(-) T cells. Furthermore, donor Møs of mixed chimeras produced more IL-10 and less IFN-γ than those of naive mice when cultured with BALB/c but not the third party C3H CD4(+) T cells. Induction of recipient CD4(+) Treg cells by donor Møs was significantly blocked by anti-IL-10, but not by anti-TGF-β mAb. Therefore, donor Møs have the ability to induce recipient CD4(+)Foxp3(+) Treg cells in a donor antigen-specific manner, at least partially, via an IL-10-dependent pathway. This study for the first time showed that, in mixed allogeneic chimeras, donor Møs could be specifically tolerant to recipients and gained the ability to induce recipient but not the third party Foxp3(+) Treg cells. Whether this approach is involved in transplant immune tolerance needs to be determined.