Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells: relevance to mechanism of heart allograft tolerance.

Abstract

We hypothesize that developmental exposure to noninherited maternal Ags (NIMA) results in alloantigen-specific natural and adaptive T regulatory (T(R)) cells. We compared offspring exposed to maternal H-2(d) (NIMA(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(+) T cells of NIMA(d)-exposed vs control splenocytes. NIMA(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(d)-exposed mice by T(R) cells to varying degrees. Some (40%) NIMA(d)-exposed mice accepted a DBA/2 allograft while others (60%) rejected in delayed fashion. Rejector and acceptor NIMA(d)-exposed mice had reduced T effector responses and increased Foxp3(+) T(R) cells (CD4(+)CD25(+)Foxp3(+) T(R)) in spleen and lymph nodes compared with controls. The key features distinguishing NIMA(d)-exposed acceptors from all other mice were: 1) higher frequency of IL-10- and TGF-beta-producing cells primarily in the CD4(+)CD25(+) T cell subset within lymph nodes and allografts, 2) a suppressed delayed-type hypersensitivity response to B6D2F1 Ags, and 3) allografts enriched in LAP(+), Foxp3(+), and CD4(+) T cells, with few CD8(+) T cells. We conclude that the beneficial NIMA effect is due to induction of NIMA-specific T(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.

Statistics

01020302008200920102011201220132014201520162017
Citations per Year

95 Citations

Semantic Scholar estimates that this publication has 95 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{MolitorDart2007DevelopmentalET, title={Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells: relevance to mechanism of heart allograft tolerance.}, author={Melanie L. Molitor-Dart and Joachim Andrassy and Jean Kwun and H{\"{u}seyin Ayhan Kayaoğlu and Drew Allan Roenneburg and Lynn D. Haynes and Jose R. Torrealba and Joseph Louis Bobadilla and Hans W . Sollinger and Stuart J Knechtle and William J. Burlingham}, journal={Journal of immunology}, year={2007}, volume={179 10}, pages={6749-61} }