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* Department of Pathology and Laboratory Medicine, Cellular and Molecular Pathology, University of Wisconsin, Madison, WI 53706;
Surgery Department Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany; and
Department of Surgery, University of Wisconsin, Madison, WI 53792
We hypothesize that developmental exposure to noninherited maternal Ags (NIMA) results in alloantigen-specific natural and adaptive T regulatory (TR) 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 TR 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 NIMAd-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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1 This work was supported by National Institutes of Health Grant RO1 AI066219 and a grant from the Division of Transplantation, Department of Surgery, UW-Madison.
2 Address correspondence and reprint requests to Dr. William J. Burlingham, University of Wisconsin, G4/702 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. E-mail address: burlingham{at}surgery.wisc.edu
3 Abbreviations used in this paper: HSC, hemopoietic stem cell; NIMA, noninherited maternal Ag; NIPA, noninherited paternal Ag; GVHD, graft-vs-host disease; TR, T regulatory; BFA, brefeldin A; LN, lymph node; DTH, delayed-type hypersensitivity; lf, limits of flocculation; TT/DT, tetanus and diphtheria toxoid; TE, T effector; DST, donor-specific transfusion; ILN, inguinal LN; GIC, graft-infiltrating cell; LAP, latency associated peptide.
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