STAT3 signaling contributes to the high effector activities of interleukin‐15‐derived dendritic cells

Abstract

Dendritic cells (DCs) are important innate and adaptive immune effectors, and have a key role in antigen presentation and T-cell activation. Different lineages of DCs can be developed from hematopoietic progenitors following cytokine signaling, and the various lineages of DCs display distinct morphology, phenotype and functions. There has been limited information on differential cytokine-mediated molecular signaling in DCs. Analyses of surface molecules by flow cytometry and quantitative RNA profiling revealed differences between DCs derived from interleukin-4 (IL-4) versus IL-15 signaling, yet both lineages of DCs exhibited similar levels of surface molecules key to immune activation. Functional assays confirmed that IL-15-derived DCs elicited greater antigen-specific, primary and secondary CD8 and CD4 T-cell responses than did IL-4-derived DCs. Importantly, IL-15 DCs secreted substantial amounts of proinflammatory cytokines, including IL-6, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNFα), which helped polarize a strong T-cell response. Assessment of signaling pathways revealed that IL-15 DCs exhibited a lower levels of activated signal transducer and activator of transcription 5 (STAT5), STAT6 and extracellular signal-regulated kinase 1/2 than IL-4 DCs, but after lipopolysaccharide (LPS)/TNFα treatment, the STAT3 and p38 mitogen-activated protein kinase (MAPK) activities were significantly enhanced in the IL-15 DCs. Surprisingly, contrary to the canonical IL-15-mediated STAT5 signaling pathway in lymphoid cells, IL-15 did not mediate a strong STAT5 or STAT3 activation in DCs. Further analysis using specific inhibitors to STAT3 and p38 MAPK pathways revealed that the STAT3 signaling, but not p38 MAPK signaling, contributed to IFN-γ production in DCs. Therefore, while IL-15 does not promote the STAT signaling in DCs, the increased STAT3 activity after LPS/TNFα treatment of the IL-15 DCs has a key role in their high IFN-γ effector activities.

Induction of antitumor cytotoxic lymphocytes using engineered human primary blood dendritic cells

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SOCS1 is a negative regulator of metabolic reprogramming during sepsis

“…Here, our data show that in the absence of SOCS1, STAT3, but not STAT1, is highly activated via phosphorylation. Further, treatment of mice with a STAT3 blocking peptide, STATTIC (39,64,65), reduces both mortality and bacterial burden in iKIR-treated septic mice. STAT3 is activated by IL-6 (66).…”

Comparison of morphology, phenotypes and function between cultured human IL-4-DC and IFN-DC

“…In recent years, many researchers have focused on the exploit of IFN-DC developed by culturing monocytes with GM-CSF and IFN-α as this DCs subset could be more effective than IL-4-DC in the aspect of antigen cross-presentation ( 26 ). Moreover, some studies revealed that the antigen presentation of IL-4-DC relied on the signal transducer and activator of transcription 6 (STAT6) while IFN-DC was not, suggesting that these two DCs have different presenting ways ( 25 , 27 , 28 ). Although IFN-DC and IL-4-DC have been studied for several years, the details of the morphology, phenotype and function of these DCs still need to be explored.…”