Prevention of Red Cell Alloimmunization by CD25 Regulatory T Cells in Mouse Models

Transfusion therapy is currently an effective therapeutic intervention in a number of diseases, including sickle cell disease. However, its use is complicated by a high incidence of red blood cell (RBC) alloimmunization in the transfusion recipients. The identification of T regulatory cells (Tregs) among the CD4(+) CD25(+) T cell subset as key regulators of peripheral tolerance in mice as well as humans has opened an exciting era in the prevention and treatment of autoimmune disease and for improving organ transplantation. However, their potential in inducing transfusion tolerance remains to be explored. We used red cells from mice transgenic for human glycophorin A blood group antigen as donor cells and transfused wild-type mice to induce alloantibodies, as an experimental system to study RBC alloimmunization. We found that depletion with anti-CD25 enhanced the alloantibody production, indicating that CD25 Tregs play an important role in regulation of alloantibody responses. More importantly, adoptive transfer of purified population of CD4(+)CD25(+) but not CD4(+)CD25(-) cells from naïve mice prevented the induction of IgG and IgM alloantibody production in transfusion recipients, with a concomitant reduction in activated splenic B cells and macrophages. Similarly, adoptive transfer of purified populations of CD4(+)CD25(+) cells from naïve mice into naïve syngeneic recipients inhibited the anti-Ig response to rat RBCs in the recipients but transfer of control CD4(+)CD25(-) cells did not. Altogether, our results demonstrate that Tregs participate in the control of transfusion-associated RBC alloantibody responses, opening up the possibility that Treg immunotherapy may be exploited for suppressing transfusion immunization events.