Human tolerogenic dendritic cells produce IL‐35 in the absence of other IL‐12 family members

KO Dixon, SW van der Kooij… - European journal of …, 2015 - Wiley Online Library
KO Dixon, SW van der Kooij, DAA Vignali, C van Kooten
European journal of immunology, 2015Wiley Online Library
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 …
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.
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