Controlling dendritic cell function by targeting iron-modulating proteins identified through transcriptional analysis
Year: 2018
Type: article
Abstract: Dendritic cells (DC) are key orchestrators of the body’s immune responses. DC control T cell proliferation and differentiation while displaying cognate antigen (Ag) to Ag-specific T cells. DC cytokine secretion is central to the differentiation of T cells into distinct, functional subsets. Stimulation with bacteria-derived molecules such as lipopolysaccharide (LPS) through Toll-like receptor 4 (TLR4) leads to interleukin-12 (IL-12) production by DC and supports T helper type 1 (Th1) generation in interacting cluster of differentiation 4 (CD4+) T cells. Fungal interactions with the Dectin-1 receptor yields IL-6, IL-23, and IL-1β production by DC to mediate Th17 cell polarization. DC, especially those exposed to IL-33, support the generation of IL-5- and IL-13- secreting Th2 cells. However, there are no identified DC-produced cytokines which have been shown to directly underlie Th2 polarization. The aim of this project was to identify novel genes and signaling pathways by which CD4+ T cell polarization is directed following DC TLR4/ST2 (IL1RL1) ligation. Our preliminary data demonstrated that IL-33 and LPS stimulate the expression of several iron-modulating proteins in DC, such as lipocalin 2 (Lcn2), hemoglobin-α, and cytochrome b5 reductase 3 (Cyb5R3), which act as a previously unappreciated DC nitric oxide (NO) sequestration system. Given these findings, we hypothesized that TLR4/ST2 ligation on DC causes expression of iron-modulating proteins which sequester NO. We found that while TLR4/ST2 receptor ligation on DC induces a NO sequestration system in DC, it involves the expression of hemoglobin-α and potentially other redundant reductase proteins, but not Cyb5R3. Instead, we determined that Cyb5R3 acts as a regulator of DC stimulatory capacity toward CD4+ T cells. Specifically, Cyb5R3 functions as a negative regulator of glycolysis. In Cyb5R3-expressing cells, unstimulated and IL-33-stimulated cells favor oxidative phosphorylation (OXPHOS) while LPS stimulation leads a shift towards glycolysis. Finally, Cyb5R3-deficient DC are both more inflammatory and more stimulatory, producing greater amounts of IL-12 and expressing more stimulatory surface markers, ultimately leading to Th1 cell polarization of naïve T cells, especially upon DC stimulation with LPS.
Author: Anna Roessing
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2899319996