Rapamycin Augments Human DC IL-12p70 and IL-27 Secretion to Promote Allogeneic Type 1 Polarization Modulated by NK Cells
Identifieur interne : 006C11 ( Main/Merge ); précédent : 006C10; suivant : 006C12Rapamycin Augments Human DC IL-12p70 and IL-27 Secretion to Promote Allogeneic Type 1 Polarization Modulated by NK Cells
Auteurs : C. Macedo [États-Unis] ; H. R. Turnquist [États-Unis] ; M. Castillo-Rama [États-Unis] ; A. F. Zahorchak [États-Unis] ; R. Shapiro [États-Unis] ; A. W. Thomson [États-Unis] ; D. Metes [États-Unis]Source :
- American journal of transplantation : (Print) [ 1600-6135 ] ; 2013.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Homme, Antibiotique.
English descriptors
- KwdEn :
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.
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<term>Antibacterial agent</term>
<term>Antibiotic</term>
<term>Antigen presenting cell</term>
<term>Antineoplastic agent</term>
<term>Dendritic cell</term>
<term>Human</term>
<term>Immunosuppressive agent</term>
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<term>Secretion</term>
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<term>Cellule NK</term>
<term>Cellule dendritique</term>
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<term>Antibiotique</term>
<term>Anticancéreux</term>
<term>Immunodépresseur</term>
<term>Antibactérien</term>
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<front><div type="abstract" xml:lang="en">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.</div>
</front>
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