Differential regulation of CD103 (αE integrin) expression in human dendritic cells by retinoic acid and Toll-like receptor ligands

Abstract

CD103 (αE 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 β7 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-β signaling in MoDCs down-regulated RA-induced CD103 expression, indicating that TGF-β-dependent pathways contribute to the induction of CD103. Conversely, when RA-treated MoDCs were stimulated with live , commensal bacteria, LPS, or a TLR2 agonist, the RA-induced up-regulation of CD103 and β7 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 CD103 DCs to induce mucosal homing and T cell proliferation. Surprisingly, RA treatment of DCs enhanced both α4β7 expression and proliferation in cocultured T cells, but no difference was seen between RA-treated CD103 and CD103 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.

Lipopolysaccharide impacts murine CD103+ DC differentiation, altering the lung DC population balance

“…Previous studies reported that GM-CSF upregulates CD103 expression on BM-derived DCs differentiated with FLT3-L in vitro, and that GM-CSF or GM-CSF receptor deficient mice display altered CD103 expression on DC1s in several organs, including the lung [25,[28][29][30][31][32]. Interestingly, previous reports show that LPS blocks CD103 expression induced by retinoic acid on human monocyte derived-DCs [33]. Therefore, we hypothesised that LPS-induced inflammation could impact the GM-CSFinduced CD103 expression on DCs upon their final maturation in the lung, and/or induce systemic alterations of pre-DCs differentiation towards the XCR1 + /CD103 + DCs, contributing to altered CD103 + DC populations following LPS exposure.…”

Helicobacter: Inflammation, immunology and vaccines

“…An additional factor in DC differentiation of Tregs is retinoic acid (RA). While RA enhanced expression of αE integrin (CD103) and mucosal homing receptor β7 in MoDCs, Roe et al . found no such effect on primary human gastric DCs, indicating strong influences of the mucosal environment.…”

p38 MAPK signaling mediates retinoic acid‐induced CD103 expression in human dendritic cells

“…21,23,27 Our previous analyses showed that RA signaling leading to CD103 expression in human DCs intersects with transforming growth factor-b (TGF-b) signaling, as a small molecule inhibitor of the TGF-b receptor prevented RA-induced CD103 up-regulation. 13 In activated CD8 T cells, TGF-b leads to strong induction of CD103 expression. 28,29 However, TGF-b alone does not drive CD103 expression in DCs, as we and others have shown, 13,17 pointing to complex interactions between RA signaling and TGF-b signaling pathways.…”

“…[9][10][11] Importantly, a significant number of animal studies have revealed an association between DC production of RA, the DC response to RA and DC expression of CD103, the a-chain of integrin a E b 7 . 7,8,[12][13][14] CD103 is a functionally important subset marker for gastrointestinal DCs in mice and is also expressed on mucosal DC subsets in humans. 7,15,16 Analyses from our laboratory and others have demonstrated that RA drives the expression of CD103 (integrin a E ) as well as the corresponding b-chain integrin b 7 on human DCs.…”

“…7,15,16 Analyses from our laboratory and others have demonstrated that RA drives the expression of CD103 (integrin a E ) as well as the corresponding b-chain integrin b 7 on human DCs. 13,17,18 Several studies in mice suggest that signaling through retinoic acid receptor a Abbreviations: cDC, conventional dendritic cell; DC, dendritic cell; integrin a E , CD103; ITGAE, CD103 gene name; ITGB7, b 7 gene name; MAPK, mitogen-activated protein kinase; MDM, monocyte-derived macrophage; MoDC, monocyte-derived dendritic cell; RA, retinoic acid; RAR, retinoic acid receptor; siRNA, small interfering RNA; TGF-b, transforming growth factor-b; TGFbRII, TGF-b receptor II…”