Fetal microchimerism persists at high levels in c-kit+ stem cells in sensitized mothers

Abstract

We previously showed that fetal and maternal exposure to non-inherited maternal antigens (NIMA) during gestation and nursing resulted in lifelong tolerance to NIMA in some offspring. This NIMA-specific tolerance was mediated by regulatory T cells (Tregs) and was correlated with the level of multi-lineage maternal microchimerism (Mc) indicating a causative link between Mc and Treg development. To determine if transfer of fetal cells into mothers resulted in a similar tolerance to fetal cells, we used qPCR to detect rare fetal derived cells and a delayed type hypersensitivity (DTH) assay to detect fetal alloantigen-specific effector and regulatory T cells in mothers. We found that 5/8 B6 mothers of H2b/d offspring were sensitized to the alloantigens H2d and HY, indicating a dominance of alloantigen-specific effector T cells. Though these sensitized mothers did not have detectable fetal Mc (FMc) in any of the organs tested, they had very high levels of fetus-derived c-kit+ stem cells in their bone marrow. The remaining 3/8 B6 mothers that were not sensitized to the fetal antigens had detectable FMc found mostly in heart, lungs and liver, and in 2/3, we could detect alloantigenspecific regulatory T cells. This data indicates that, as in NIMA-specific tolerance, tolerance in multiparous females to inherited paternal antigens (IP A) expressed by the fetus is associated with the presence of fetal Mc in differentiated cell subsets. Surprisingly, robust lin-c-kit+ bone marrow cell fetal Mc can occur in sensitized mothers. This suggests a continuous source of allospecific priming, coupled with active elimination of mature IP A-expressing lin+ cells by effector T cells of the maternal host. © 2010 Landes Bioscience.