title: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Cellular and Molecular Pathology, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Molitor-Dart
authors.forename: Joachim
authors.initials: J
authors.lastname: Andrassy
authors.forename: Jean
authors.initials: J
authors.lastname: Kwun
authors.forename: H Ayhan
authors.initials: HA
authors.lastname: Kayaoglu
authors.forename: Drew A
authors.initials: DA
authors.lastname: Roenneburg
authors.forename: Lynn D
authors.initials: LD
authors.lastname: Haynes
authors.forename: Jose R
authors.initials: JR
authors.lastname: Torrealba
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Bobadilla
authors.forename: Hans W
authors.initials: HW
authors.lastname: Sollinger
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Knechtle
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D024201:Bystander Effect / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism; D006183:H-2 Antigens / Q000096:biosynthesis / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D054502:Histocompatibility, Maternal-Fetal / Q000276:immunology*; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007519:Isoantigens / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013745:Tetanus Toxoid / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology; D014181:Transplantation Immunology; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006183:H-2 Antigens; D007519:Isoantigens; D013745:Tetanus Toxoid; D016212:Transforming Growth Factor beta; D016753:Interleukin-10