Single blood transfusion induces the production of donor-specific alloantibodies and regulatory T cells mainly in the spleen

Abstract

Donor-specific blood transfusion is known to induce alloresponses and lead to immunosuppression. We examined their underlying mechanisms by employing fully allogeneic rat combinations. Transfused recipients efficiently produced alloantibodies of the IgM and IgG subclasses directed against donor class I MHC. The recipients exhibited active expansion of CD4⁺ T cells and CD4⁺FOXP3⁺ regulatory T cells (T_reg cells), followed by CD45R⁺ B cells and IgM⁺ or IgG subclass⁺ antibody-forming cells mainly in the spleen. From 1.5 days, the resident MHCII⁺CD103⁺ dendritic cells (DCs) in the splenic T-cell area, periarterial lymphocyte sheath, formed clusters with recipient BrdU⁺ or 5-ethynyl-2′-deoxyuridine⁺ cells, from which the proliferative response of CD4⁺ T cells originated peaking at 3–4 days. Transfusion-induced antibodies had donor passenger cell-depleting activity in vitro and in vivo and could suppress acute GvH disease caused by donor T cells. Furthermore, T_reg cells significantly suppressed mixed leukocyte reactions in a donor-specific manner. In conclusion, single blood transfusion efficiently induced a helper T-cell-dependent anti-donor class I MHC antibody-forming cell response with immunoglobulin class switching, and a donor-specific T_reg cell response mainly in the spleen, probably by way of the indirect allorecognition via resident DCs. These antibodies and T_reg cells may be involved, at least partly, in the donor-specific transfusion-induced suppression of allograft rejection.