STAT3-silenced human dendritic cells have an enhanced ability to prime IFNγ production by both αß and γδ T lymphocytes.

Dendritic cells (DC) are an attractive target for therapeutic manipulation of the immune system to enhance insufficient immune responses, such those occurring in cancer, or to dampen dangerous responses in allergic and autoimmune diseases. Main goal of this study was to manipulate human monocyte-derived DC (MDDC) function by silencing STAT3, since this transcription factor plays a key role as a negative regulator of immune surveillance, and is strongly involved in inflammation. STAT3 silencing did not affect the immunophenotype of both immature and toll-like receptor (TLR) ligand-matured DC. However, an altered cytokine secretion profile, characterized by lower IL10 and higher IL12 and TNFα levels, was observed in silenced DC with respect to control cells upon TLR triggering. Accordingly, STAT3 silenced MDDC promoted a higher IFNγ production by CD4(+) naïve T cells. Furthermore, STAT3 silencing in MDDC favored the activation of γδ T lymphocytes, an immune cell population with important antitumor effector activities. This effect was at least in part mediated by the increased IL12 production by silenced cells. STAT3 silencing also increased the levels of CCL4, a CCR5-binding chemokine known to be involved in T helper 1 (Th1) cell recruitment. Altogether these results strengthen the role of STAT3 as a critical check point of the suppression of Th1 responses, unraveling its potential to dampen DC capability to both induce and recruit different IFNγ producing T lymphocyte subsets.

CCL2 induction by 1,25(OH)2D3 in dendritic cells from healthy donors and multiple sclerosis patients.

CCL2 plays a pivotal role in the recruitment of different immune cells to sites of inflammation and evidence indicates its involvement in multiple sclerosis (MS) pathogenesis. MS lesions are characterized by an inflammatory infiltrate, whose nature is controlled by chemokines and cytokines, and elevated expression of CCL2 has been found in acute and chronic MS plaques within the brain. Vitamin D deficiency is currently considered one of the main environmental MS risk factors. In this study we analyzed the role of 1,25(OH)2D3, the bioactive vitamin D metabolite, in the regulation of CCL2 expression by dendritic cells (DC) obtained from healthy donors and relapsing-remitting MS patients. We report that 1,25(OH)2D3, as well as 25OHD3, its main blood precursor, induce the secretion of high levels of CCL2. 1,25(OH)2D3-induced CCL2 levels are comparable to those secreted in response to a classical DC maturation stimulus. Moreover, we observed that 1,25(OH)2D3 is able to induce a significant CCL2 secretion in DC obtained from relapsing-remitting MS patients, although CCL2 levels in these latter are lower with respect to healthy controls. The cause(s) of this apparently defective response of DC from patients and its consequences in the context of MS remain to be elucidated. However, we propose CCL2 as a molecular player contributing to the immunomodulatory activity of 1,25(OH)2D3 on DC, and hypothesize a role for this chemokine in the response of MS patients to vitamin D therapy. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

Dissecting TLR3 signalling in dendritic cells.

Toll-like receptor (TLR) 3 recognizes double-stranded RNA and triggers the production of type 1 interferon and inflammatory cytokines/chemokines. Its engagement in dendritic cells (DCs) induces their maturation into potent immunostimulatory cells endowed with the capacity to efficiently cross-prime T lymphocytes. Owing to these properties, TLR3 agonists are currently under investigation as promising adjuvants in DC-based immunotherapy protocols for the treatment of viral and neoplastic diseases. Thus, a detailed understanding of the cascade of events specifically triggered in DCs upon engagement of this receptor is of great interest in translational research. In this review, we summarize the current knowledge on TLR3 signalling in DCs and highlight similarities and differences with respect to other cell types.