title: Rapamycin augments human DC IL-12p70 and IL-27 secretion to promote allogeneic Type 1 polarization modulated by NK cells.
abstract: Mammalian target of rapamycin kinase inhibitor (mTORi) rapamycin (RAPA) use in transplantation can lead to inflammatory complications in some patients. Our goal was to better understand how mTORi-exposed human monocyte-derived dendritic cells (DC) stimulated with pro-inflammatory cytokines shape T cell allo-immunity. RAPA-conditioned-DC (RAPA-DC) displayed a more immature phenotype than untreated, control (CTRL)-DC. However, subsequent exposure of RAPA-DC to an inflammatory cytokine cocktail (ICC) plus IFN-γ induced a mature Type-1 promoting phenotype, consisting of elevated HLA-DR and co-stimulatory molecules, augmented IL-12p70 and IL-27 production, but decreased IL-10 secretion compared to CTRL-DC. Co-culture of mature (m)RAPA-DC with allogeneic peripheral blood mononuclear cells resulted in significantly increased Type-1 (IFN-γ) responses by T cells. Moreover, NK cells acted as innate modulators that conveyed activating cell-to-cell contact signals in addition to helper (IFN-γ) and/or regulatory (IL-10) soluble cytokines. We conclude that production of IL12-p70, IL-27 and low IL-10 by RAPA-DC allowed us to elucidate how these cytokines as well as NK-DC interaction shapes T cell allo-immunity. Thus, lack of inhibitory NK cell function during allo-specific T cell activation by human ICC + IFN-γ-stimulated RAPA-DC may represent an unwanted effector mechanism that may underlie RAPA-induced inflammatory events in transplant patients undergoing microbial infection or allograft rejection.
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, Pittsburgh, PA.
authors.forename: C
authors.initials: C
authors.lastname: Macedo
authors.forename: H R
authors.initials: HR
authors.lastname: Turnquist
authors.forename: M
authors.initials: M
authors.lastname: Castillo-Rama
authors.forename: A F
authors.initials: AF
authors.lastname: Zahorchak
authors.forename: R
authors.initials: R
authors.lastname: Shapiro
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
authors.forename: D
authors.initials: D
authors.lastname: Metes
mesh_terms: D002454:Cell Differentiation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism*; D064094:Interleukin-27 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C508609:IL10 protein, human; D064094:Interleukin-27; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D020123:Sirolimus
keywords: Dendritic cells; NK cells; human; rapamycin
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