Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Bidirectional cell transfer during pregnancy frequently leads to postpartum persistence of allogeneic cells and alloimmune responses in both the mother and in her offspring. The life-long consequences of naturally acquired alloimmune reactivity are probably of importance for the outcome of allogeneic stem cell transplantation. We investigated the presence of CD8^pos minor histocompatibility (H) antigen-specific cytotoxic T lymphocytes (TCTL) and CD8^pos minor H antigen-specific T regulator cells (T_REG) in peripheral blood cells obtained from 17 minor H antigen-disparate mother-offspring pairs. Absence of minor H antigen-specific T_REG, as marked by the feasibility to expand T_CTL from isolated tetramer ^pos populations, was observed in 6 mothers and 1 son. The presence of minor H alloantigen-specific T_REG was observed in 4 mothers and 5 sons. These T_REG were detected within isolated tetramer^dim staining fractions and functioned in a CTLA-4-dependent fashion. Our study indicates that both T_CTL and T_REG mediated alloimmunity against minor H antigens may be present in healthy female and male hematopoietic stem cell donors, potentially influencing graft-versus-host reactivity in different ways.