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Originally published online as doi:10.1189/jlb.1007716 on July 8, 2008

Published online before print July 8, 2008
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(Journal of Leukocyte Biology. 2008;84:1057-1064.)
© 2008 by Society for Leukocyte Biology

Induction of human CD4+ regulatory T cells by mycophenolic acid-treated dendritic cells

Christine Lagaraine*,1,2, Roxane Lemoine*,1, Christophe Baron*, Hubert Nivet*, Florence Velge-Roussel*,{dagger} and Yvon Lebranchu*

* JE 2448, "Cellules Dendritiques et Greffes," and
{dagger} UFR des Sciences Pharmaceutiques, Université François-Rabelais de Tours, Tours, France

2 Correspondence: Université Francois-Rabelais de Tours, JE 2448, "Cellules Dendritiques et Greffes," 10 Bd Tonnelle, Tours, 37000, France. E-mail: lebranchu{at}med.univ-tours.fr

Depending on their degree of maturation, costimulatory molecule expression, and cytokine secretion, dendritic cells (DC) can induce immunity or tolerance. DC treated with mycophenolic acid during their maturation (MPA-DC) have a regulatory phenotype and may therefore provide a new approach to induce allograft tolerance. Purified CD4+ T cells stimulated in a human in vitro model of mixed culture by allogeneic MPA-DC displayed much weaker proliferation than T cells activated by mature DC and were anergic. This hyporesponsiveness was alloantigen-specific. Interestingly, T cells stimulated by MPA-DC during long-term coculture in four 7-day cycles displayed potent, suppressive activity, as revealed by marked inhibition of the proliferation of naive and preactivated control T cells. These regulatory T cells (Tregs) appeared to have antigen specificity and were contact-dependent. Tregs induced by MPA-DC were CD25+glucocorticoid-induced TNFR+CTLA-4+CD95+, secreted IL-5 and large amounts of IL-10 and TGF-β, and displayed enhanced forkhead box p3 expression. These results obtained in vitro demonstrate that human MPA-DC can induce allospecific Tregs that may be exploited in cell therapy to induce allograft tolerance.

Key Words: tolerance • suppression • T lymphocytes