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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.

Type

Journal article

Journal

J Immunol

Publication Date

15/05/2004

Volume

172

Pages

6003 - 6010

Keywords

Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antigens, CD4, CD4-Positive T-Lymphocytes, Cell Division, Clonal Deletion, Clone Cells, DEAD-box RNA Helicases, Female, Glucocorticoid-Induced TNFR-Related Protein, Growth Inhibitors, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Mice, Transgenic, Minor Histocompatibility Antigens, Molecular Sequence Data, Proteins, Receptors, Antigen, T-Cell, Receptors, Nerve Growth Factor, Receptors, Tumor Necrosis Factor, Skin Transplantation, T-Lymphocyte Subsets, Transforming Growth Factor beta, Transplantation Tolerance