title: Induction of human CD4+ regulatory T cells by mycophenolic acid-treated dendritic cells.
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-beta, 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.
authors.affiliation: Cellules Dendritiques et Greffes, Universite Francois-Rabelais de Tours, Tours, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lagaraine
authors.forename: Roxane
authors.initials: R
authors.lastname: Lemoine
authors.forename: Christophe
authors.initials: C
authors.lastname: Baron
authors.forename: Hubert
authors.initials: H
authors.lastname: Nivet
authors.forename: Florence
authors.initials: F
authors.lastname: Velge-Roussel
authors.forename: Yvon
authors.initials: Y
authors.lastname: Lebranchu
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency / Q000276:immunology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology
chemical_list: D016207:Cytokines; D017931:DNA Primers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D009173:Mycophenolic Acid