Inducing cell-intrinsic dysfunction in pregnancy-sensitized alloreactive B cells

Abstract

Abstract Objective: Pregnancy is an immunological paradox where the maternal immune system develops tolerance to semi-allogeneic fetus yet is a sensitizing event that is detrimental to subsequent organ transplantation. Humoral sensitization by semi-allogeneic pregnancy in WT mice prevents anti-CD154-mediated tolerance to fetus matched allograft. In contrast, pregnancy in mice lacking secreted immunoglobulins (mIgM −/−AID −/−; SIgKO) permitted anti-CD154 mediated transplant tolerance, suggesting that fetus-specific antibodies (FSA) were mediating resistance to anti-CD154. Here, we tested whether pregnancy-induced memory B cells could be desensitized to acquire a state of cell-intrinsic dysfunction. Methods: Pregnancy-sensitized SIgKO or WT mice were subjected to fetus-matched heart transplant/anti-CD154 (PP-tolerant B) or not (PP-memory B). Enriched B cells were adoptively transferred (AdTr) into secondary hosts (MD4 mice) and challenged with fetus-matched splenocytes. Germinal center (GC) allo-reactive B cells from MD4 mice were identified with MHC tetramers, and Fas +GL7 +. Results: While SIgKO PP-memory B cells differentiated into GC-B cells in secondary hosts; this was significantly decreased by 7–10-fold in SIgKO PP-tolerant B cells. In contrast, WT PP-memory B cells and PP-tolerant B cells comparably differentiated into GC-B cells. Conclusions: In the absence of FSA, PP memory B cells can acquire a cell-intrinsic hypo-functional state. This suggests possible B cell desensitization for multiparous women, who are currently disadvantaged by pregnancy-induced humoral sensitization. R01AI42747, P01AI097113