Induction of foxP3+ Regulatory T Cells in the Periphery of T Cell Receptor Transgenic Mice Tolerized to Transplants

• Published in: The Journal of immunology (1950) Vol. 172; no. 10; pp. 6003 - 6010
• Main Authors: Cobbold, Stephen P, Castejon, Raquel, Adams, Elizabeth, Zelenika, Diana, Graca, Luis, Humm, Susan, Waldmann, Herman
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.05.2004
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; CD4 Antigens - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Division - genetics; Cell Division - immunology; Clonal Deletion - genetics; Clone Cells; DEAD-box RNA Helicases; Female; Glucocorticoid-Induced TNFR-Related Protein; Growth Inhibitors - pharmacology; Lymphocyte Activation - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Transgenic; Minor Histocompatibility Antigens; Molecular Sequence Data; Proteins - immunology; Receptors, Antigen, T-Cell - genetics; Receptors, Nerve Growth Factor - biosynthesis; Receptors, Tumor Necrosis Factor - biosynthesis; Skin Transplantation - immunology; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Transforming Growth Factor beta - physiology; Transplantation Tolerance - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.172.10.6003

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.