TY - JOUR
T1 - Developmental exposure to noninherited maternal antigens induces CD4 + T regulatory cells
T2 - Relevance to mechanism of heart allograft tolerance
AU - Molitor-Dart, Melanie L.
AU - Andrassy, Joachim
AU - Kwun, Jean
AU - Kayaoglu, H. Ayhan
AU - Roenneburg, Drew A.
AU - Haynes, Lynn D.
AU - Torrealba, Jose R.
AU - Bobadilla, Joseph L.
AU - Sollinger, Hans W.
AU - Knechtle, Stuart J.
AU - Burlingham, William J.
PY - 2007/11/15
Y1 - 2007/11/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.179.10.6749
DO - 10.4049/jimmunol.179.10.6749
M3 - Article
C2 - 17982065
AN - SCOPUS:38449087281
SN - 0022-1767
VL - 179
SP - 6749
EP - 6761
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -