Browsing by Author "Sewell, Marisa A."

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CD103 regulation in human dendritic cells using retinoic acid in the gastric microenvironmnet
(Montana State Univeristy, 2017-04) Sewell, Marisa A.
CD103 (αE integrin) is an important marker for dendritic cells (DCs) in the human mucosa. Iliev et. al (2016) showed that CD103+ DCs display tolerogenic behavior in the human gut and induce Treg cell development. However, not much is known about the regulation of its expression, though it is widely used as a delineator of DC populations. Previous work in my group shows that retinoic acid (RA) and toll-like receptor agonists contribute to the regulation of CD103 expression in human DCs (Roe et al, 2016). We postulate that CD103 functions to initiate DC binding to gastric epithelium, possibly to E-cadherin, in order to allow for antigen sampling through tight junctions by DC dendrites. Additionally, previous research in this lab has concerned the identification of gastric stromal factors using gastric stroma- conditioned media (SCM), which is a model for the gastric microenvironment. I have shown that gastric stromal factors are responsible for suppressing dendritic cell maturation in Helicobacter pylori infection. We have thus confirmed SCM-derived immunoregulatory factors as a suitable model for generating dendritic cells with a tolerogenic mucosal phenotype. Here, we’ve confirmed that (RA) induces CD103 expression in peripheral-blood monocyte derived dendritic cells (MoDCs). Additionally, we show that the addition of SCM increases the extracellular expression of CD103 in both RA and non RA treated conditions. Lastly, I show that intracellular concentrations of CD103 in the presence of SCM are lower than extracellular concentrations, whereas CD103 is predominantly located in the cytoplasm in the absence of SCM, indicating that SCM may be a catalyst for initiating redistribution of CD103 to the cell membrane.
Differential regulation of CD103 (alphaE integrin) expression in human dendritic cells by retinoic acid and Toll-like receptor ligands
(2017-05) Roe, Mandi M.; Swain, Steve; Sebrell, T. Andrew; Sewell, Marisa A.; Collins, Madison M.; Perrino, Brian A.; Smith, Phillip D.; Smythies, Lesley E.; Bimczok, Diane
CD103 (alphaE integrin) is an important dendritic cell (DC) marker that characterizes functionally distinct DC subsets in mice and humans. However, the mechanism by which CD103 expression is regulated in human DCs and the role of CD103 for DC function are not very well understood. Here, we show that retinoic acid (RA) treatment of human monocyte-derived DCs (MoDCs) increased the ability of the DCs to synthesize RA and induced MoDC expression of CD103 and beta7 at the mRNA and protein level. In contrast, RA was unable to induce the expression of CD103 in primary human DCs isolated from the gastric mucosa. Inhibition of TGF-beta signaling in MoDCs down-regulated RA-induced CD103 expression, indicating that TGF-beta-dependent pathways contribute to the induction of CD103. Conversely, when RA-treated MoDCs were stimulated with live Helicobacter pylori, commensal bacteria, LPS, or a TLR2 agonist, the RA-induced up-regulation of CD103 and beta7 integrin expression was completely abrogated. To determine whether CD103 expression impacts DC priming of CD4+ T cells, we next investigated the ability of CD103+ and CD103â”€ DCs to induce mucosal homing and T cell proliferation. Surprisingly, RA treatment of DCs enhanced both alpha4beta7 expression and proliferation in cocultured T cells, but no difference was seen between RA-treated CD103+ and CD103â”€ DCs. In summary, our data demonstrate that RA, bacterial products, and the tissue environment all contribute to the regulation of CD103 on human DCs and that DC induction of mucosal homing in T cells is RA dependent but not CD103 dependent.