title: Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants.
abstract: Transplantation tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired tolerance was dominant, such that naive monospecific T cells were not able to override tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining transplantation tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.
authors.affiliation: Sir William Dunn School of Pathology, Oxford, UK. stephen.cobbold@path.ox.ac.uk
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Cobbold
authors.forename: Raquel
authors.initials: R
authors.lastname: Castejon
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Adams
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: Luis
authors.initials: L
authors.lastname: Graca
authors.forename: Susan
authors.initials: S
authors.lastname: Humm
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D017637:Clonal Deletion / Q000235:genetics; D002999:Clone Cells; D053487:DEAD-box RNA Helicases; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006131:Growth Inhibitors / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D011506:Proteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology; D023001:Transplantation Tolerance / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006131:Growth Inhibitors; D015778:Minor Histocompatibility Antigens; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D016212:Transforming Growth Factor beta; C115600:Ddx3y protein, mouse; D053487:DEAD-box RNA Helicases