Affinity-Dependent Alterations of Mouse B Cell Development by Noninherited Maternal Antigen1

Abstract

We have examined the passage of maternal cells into the fetus during the gestation and postpartum in mice. Using enhanced green fluorescent protein (EGFP)-transgenic females, we showed that maternal cells frequently gain access to the fetus, mostly in syngeneic pregnancies, but also in allogeneic and outbred crosses. EGFP-transgenic cells, including B, T, and natural killer cells, can persist until adulthood, primarily in bone marrow and thymus. We then asked whether maternal cells, bearing antigens not inherited by the fetus, influence the development of fetal and neonatal B lymphocytes. We have used the B cell receptor 3-83 mu/delta transgenic mouse model, whose B cells recognize the major histocompatibility complex class I molecules H-2Kk and H-2Kb, with a high or moderate affinity, respectively. The fate of transgenic B cells in animals exposed to noninherited H-2Kk or H-2Kb maternal antigens (NIMA) during gestation and lactation was compared with those of nonexposed controls. In H-2Kk-exposed fetuses, NIMA-specific transgenic B cells are partially deleted during late gestation. Nondeleted cells have downmodulated their B cell receptor. In contrast, in NIMA H-2Kb-exposed neonates, transgenic B cells present an activated phenotype, including proliferation, upregulation of surface CD69, and preferential localization in the T cell zone of splenic follicles. This state of activation is still clearly detectable up to 3 wk of age. Thus, we show that fetal and neonatal B cell development is affected by maternal cells bearing antigens noninherited by the fetus and that this phenomenon is highly dependent on the affinity of the B cell receptor for the NIMA.

Developmental Exposure to Noninherited Maternal Antigens Induces CD4+ T Regulatory Cells: Relevance to Mechanism of Heart Allograft Tolerance

“…Mothers expressing H-2 k or H-2 b Ags did not tolerize offspring that failed to inherit these Ags (J. Andrassy and M. L. Molitor-Dart, submitted for publication). Similarly, interstrain differences in NIMA effect were noted by Vernochet et al (54) who found that maternal cells influence the development of fetal and neonatal allospecific B cells, and that affinity played a large role in the outcome of this maternal influence.…”

Protective effect of noninherited maternal HLA-DR antigens on rheumatoid arthritis development

“…Maternal microchimerism has been shown in mice to induce neonatal B cell (26) and probably also T cell (27) tolerance and is therefore one of the possible mechanisms for NIMA effects (28). Although speculative, we postulate therefore that the protective effect of the DERAA-containing HLA-DRB1 alleles as NIMA on the development of RA is most probably mediated by maternal cells entering the bloodstream and tissues of the child, which exert their effect through a change in the immune repertoire and, most likely, the T cell repertoire of the child.…”

Fetal tolerance to maternal antigens improves the outcome of allogeneic bone marrow transplantation by a CD4+CD25+ T-cell–dependent mechanism

“…However, this needs to be investigated in different strain combinations because in a recent study using a transgenic mouse model, exposure to NIMAs was shown to either down-regulate or upregulate the allogeneic B-cell responses depending on the NIMA haplotypes. 18 In contrast to the NIMA effects, it remains controversial whether the maternal exposure to IPAs induces tolerance in clinical transplantation. 19 Survival rates after BMT from a maternal donor were better than those after BMT from a paternal donor.…”