title: Human tolerogenic dendritic cells produce IL-35 in the absence of other IL-12 family members.
abstract: IL-35 is a cytokine of the IL-12 family, existing as a heterodimer of IL-12p35 and Ebi3. IL-35 has anti-inflammatory properties and is produced by regulatory T cells in humans and mice, where it is required for optimal suppression of immune responses. Distinct from other IL-12 cytokines, the expression of IL-35 has not been described in antigen-presenting cells. In view of the immune-regulatory properties of IL-35, we investigated the expression, regulation, and function of IL-12p35 and Ebi3 in human monocyte-derived dendritic cells and tolerogenic DCs (tolDCs). These tolDCs do not produce IL-12p70 or the homodimer IL-12p40. We demonstrate that tolDCs completely lack transcriptional expression of IL-12p40. However, tolDCs maintain mRNA expression of IL-12p35 and Ebi3. Using intracellular flow cytometry and Western blot analysis, we show that tolDCs produce Ebi3 and IL-12p35, and both can be enhanced upon stimulation with IFN-γ, LPS, or CD40L. tolDCs supernatants have the capacity to suppress T-cell activation. Using IL12A silencing, we demonstrate that IL-12p35 is required for tolDCs to reach their full suppressive potential. Taken together, our results indicate that tolDCs produce IL-35, providing an additional novel mechanism by which tolDCs elicit their tolerogenic potential.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Karen O
authors.initials: KO
authors.lastname: Dixon
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sandra W
authors.initials: SW
authors.lastname: van der Kooij
authors.affiliation: Department of Immunology, University of Pittsburgh, PA, USA.
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D060887:B7 Antigens / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D018664:Interleukin-12 / Q000096:biosynthesis; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000378:metabolism; D064094:Interleukin-27 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D015778:Minor Histocompatibility Antigens; D010641:Phenotype
chemical_list: D060887:B7 Antigens; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C097732:EBI3 protein, human; D053765:Interleukin-12 Subunit p35; D064094:Interleukin-27; D007378:Interleukins; D008070:Lipopolysaccharides; D015778:Minor Histocompatibility Antigens; C532417:interleukin-35, human; D018664:Interleukin-12; D003907:Dexamethasone
keywords: Dendritic cells; Human; IL-12/IL-35 axis; Tolerance
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