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

We hypothesize that developmental exposure to noninherited maternal Ags (NIMA) results in alloantigen-specific natural and adaptive T regulatory (T sub(R)) cells. We compared offspring exposed to maternal H-2 super(d) (NIMA super(d)) with nonexposed controls. In vitro assays did not reveal any differences in T cell responses pretransplant. Adoptive transfer assays revealed lower lymphoproliferation and greater cell surface TGF- beta expression on CD4 super(+) T cells of NIMA super(d)-exposed vs control splenocytes. NIMA super(d)-exposed splenocytes exhibited bystander suppression of tetanus-specific delayed-type hypersensitivity responses, which was reversed with Abs to TGF- beta and IL-10. Allospecific T effector cells were induced in all mice upon i.v. challenge with B6D2F1 splenocytes or a DBA/2 heart transplant, but were controlled in NIMA super(d)-exposed mice by T sub(R) cells to varying degrees. Some (40%) NIMA super(d)-exposed mice accepted a DBA/2 allograft while others (60%) rejected in delayed fashion. Rejector and acceptor NIMA super(d)-exposed mice had reduced T effector responses and increased Foxp3 super(+) T sub(R) cells (CD4 super(+)CD25 super(+)Foxp3 super(+) T sub(R)) in spleen and lymph nodes compared with controls. The key features distinguishing NIMA super(d)-exposed acceptors from all other mice were: 1) higher frequency of IL-10- and TGF- beta -producing cells primarily in the CD4 super(+)CD25 super(+) T cell subset within lymph nodes and allografts, 2) a suppressed delayed-type hypersensitivity response to B6D2F1 Ags, and 3) allografts enriched in LAP super(+), Foxp3 super(+), and CD4 super(+) T cells, with few CD8 super(+) T cells. We conclude that the beneficial NIMA effect is due to induction of NIMA-specific T sub(R) cells during ontogeny. Their persistence in the adult, and the ability of the host to mobilize them to the graft, may determine whether NIMA-specific tolerance is achieved.