Tolerance to Noninherited Maternal MHC Antigens in Mice

The phenomenon of tolerance to noninherited maternal Ags (NIMA) is poorly understood. To analyze the NIMA effect C57BL/6 (H-2^b/b) males were mated with B6D2F₁ (H-2^b/d) females, whereby 50% of the offspring are H-2^b/b mice that have been exposed to maternal H-2 ^d alloantigens. Controls were H-2^b/b offspring of C57BL/6 mothers, either inbred C57BL/6 mice or F₁ backcross mice from breedings with H-2^b/d fathers. We found that 57% of the H-2 ^b/b offspring of semiallogeneic (H-2^b/d) mothers accepted fully allogeneic DBA/2 (H-2^d/d) heart grafts for >180 days, while similar transplants were all rejected by day 11 in controls (p < 0.0004). Foster nursing studies showed that both oral and in utero exposure to NIMA are required for this tolerogenic effect. An effect of NIMA was also found to extend the survival of skin grafts from a semiallogeneic donor (p < 0.02). Pretransplant analysis of splenocytes showed a 40-90% reduction of IL-2-, IL-5-, and IFN-γ-producing T cells responding to H-2^d-expressing APC in NIMA^d-exposed vs control mice. Injection of pregnant BALB/c-dm2 (H-2L^d-negative) female mice i.v. with H-2L^d _61-80 peptide profoundly suppressed the offspring's indirect pathway alloreactive CD4⁺ T cell response to H-2L^d. These results suggest that the natural exposure of the fetus and newborn to maternal cells and/or soluble MHC Ags suppresses NIMA-allospecific T cells of the offspring, predisposing to organ transplant tolerance in adult mice.