*Purpose: There are ample clinical data that a major long-term consequence of pregnancy is humoral allosensitization. Paradoxically, pregnancy is also a state of spontaneous allogeneic tolerance, which in mouse models is dependent on fetal-specific regulatory T cell (Treg) expansion and T cell anergy. In this study, we sought to determine if pregnancy promotes or prevents tolerance to allografts sharing MHC and non-MHC antigens with the allogeneic fetus.

*Methods: Female WT B/6 mice were mated (sensitized) with male B/c mice. At post-partum (PP) day 30-45, F1 (B/6 x B/c) heart transplants (HTx) were performed. We also used B/6 µKO (no B cells) and sIgKO (no antibodies) mice as HTx recipients.

*Results: In pregnancy-sensitized WT mice, F1-reactive Tregs and Tconv expanded compared to their naïve counterparts but did not acquire IFNγ production. Pregnancy also induced donor-specific antibodies (DSA) comparable to levels observed in recipients of F1 skin grafts. To assess pregnancy-induced alloreactive T cell tolerance, we transplanted F1 hearts (F1 HTx) into PP µKO mice and observed spontaneous F1 HTx acceptance, in contrast to acute rejection in PP WT or unsensitized µKO recipients, demonstrating disruption of PP alloreactive T cell by B cells. Furthermore, PP sIgKO mice rejected F1 HTx, suggesting that B cell functions without secreted DSA were sufficient to prevent pregnancy-induced F1-specific T cell tolerance. Transfer of B cells from PP sIgKO mice into unsensitized µKO mice prevented F1 HTx acceptance, while depleting B cells in PP sIgKO with anti-CD20 at the time of HTx promoted F1 HTx acceptance, demonstrating the necessity B cells and sufficiency of antibody-independent functions in driving PP allosensitization and resistance to induction of transplantation tolerance.

*Conclusions: Our observations suggest that pregnancy tolerizes fetal-specific T cell responses while sensitizing humoral responses. Furthermore, pregnancy-sensitized B cells overcome T cell dysfunction at the time of F1 heart transplantation causing allograft rejection. These observations underscore the need for therapies targeting B cells to reveal T cell tolerance in multiparous females, and to improve their access to transplantation with better graft outcomes.

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