Activation and migration characteristics of intestinal dendritic cell subsets
Abstract
The intestine is continuously challenged to generate protective immunity against harmful antigens, such as pathogens, and tolerance against harmless materials, such as food. Dendritic cells (DCs) are key regulators of innate and adaptive immune responses and play important roles in the generation of immunity to intestinal antigens. DCs acquire antigen in the periphery and migrate to draining lymph nodes where they prime immune responses. Different DC subsets differ in their capacity to induce distinct immune responses and this is thought to be in part due to differential expression of pattern recognition receptors (PRRs). Targeting specific DC subsets has been exploited in vaccination strategies in order to develop more efficient, targeted therapies. However, little is known about the specific requirements for activation and migration of different DC subsets. Herein, we hypothesized that distinct intestinal DC subsets differ in their migratory patterns following stimulation with poly(I:C), a synthetic analog of dsRNA signaling through TLR3. Although TLR3 is highly expressed in cDC1, poly(I:C) induced migration of cDC1 and cDC2 equally in a cell-extrinsic, TLR3 dependent manner. TLR3 activation by poly(I:C) induced early expression of pro-inflammatory cytokines, including type I IFNs, TNF-α and IL-1β. By using different genetic mouse models, we found that TNF-α was required for migration of both cDC1 and cDC2 in response to poly(I:C). However, we also detected a previously unrecognized role for intrinsic type I IFN signaling in cDC1 but not cDC2 activation and migration in response to poly(I:C). Stimulation with R848, a TLR7 ligand, showed similar results, suggesting type I IFN as a signal required for activation and migration of cDC1 in response to different TLR ligands. In contrast, IL-1β signaling was dispensable for migration. In addition, we found that pDCs were not required as a cellular source for type I IFN and TNF-α in the context of poly(I:C) injection. Preliminary studies suggest a role for macrophages instead, but future experiments are needed to confirm these facts. Collectively, these findings suggest distinct requirements for migration of DC subsets in response to poly(I:C). Future experiments assessing the functionality of cis vs trans-activated DCs will elucidate whether the observed differences on DC subset migration translate into different immune responses.
Info
Thesis PhD, 2019
UN SDG Classification
DK Main Research Area
Science/Technology
