(Journal Article): Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants.
 
Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, Waldmann H (Sir William Dunn School of Pathology, Oxford, UK., stephen.cobbold@path.ox.ac.uk )
 
IN: J Immunol 2004; 172:6003-6010
Impact Factor(s) of J Immunol: 6.486 (2004), 6.702 (2003), 7.065 (2001)

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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.

TYPE OF PUBLICATION: Original article

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