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

Melanie L. Molitor-Dart, Joachim Andrassy, Jean Kwun, H. Ayhan Kayaoglu, Drew A. Roenneburg, Lynn D. Haynes, Jose R. Torrealba, Joseph L. Bobadilla, Hans W. Sollinger, Stuart J. Knechtle, William J. Burlingham

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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-2d (NIMAd) 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-β expression on CD4+ T cells of NIMAd-exposed vs control splenocytes. NIMAd-exposed splenocytes exhibited bystander suppression of tetanus-specific delayed-type hypersensitivity responses, which was reversed with Abs to TGF-β 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 NIMAd-exposed mice by T R cells to varying degrees. Some (40%) NIMAd-exposed mice accepted a DBA/2 allograft while others (60%) rejected in delayed fashion. Rejector and acceptor NIMAd-exposed mice had reduced T effector responses and increased Foxp3+ TR cells (CD4 +CD25+Foxp3+ TR) 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-β-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 TR 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.

Original languageEnglish (US)
Pages (from-to)6749-6761
Number of pages13
JournalJournal of Immunology
Volume179
Issue number10
DOIs
StatePublished - Nov 15 2007

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Molitor-Dart, M. L., Andrassy, J., Kwun, J., Kayaoglu, H. A., Roenneburg, D. A., Haynes, L. D., Torrealba, J. R., Bobadilla, J. L., Sollinger, H. W., Knechtle, S. J., & Burlingham, W. J. (2007). Developmental exposure to noninherited maternal antigens induces CD4 + T regulatory cells: Relevance to mechanism of heart allograft tolerance. Journal of Immunology, 179(10), 6749-6761. https://doi.org/10.4049/jimmunol.179.10.6749