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Published online before print July 8, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1007716

Received for publication October 26, 2007.
Revised April 21, 2008.
Accepted for publication May 11, 2008.

Article

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

Christine Lagaraine ^*, Roxane Lemoine ^*, Christophe Baron ^*, Hubert Nivet ^*, Florence Velge-Roussel ^*, and Yvon Lebranchu ^*@

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

^@ To whom correspondence should be addressed. E-mail: lebranchu{at}med.univ-tours.fr.

	Abstract

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-, 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