Skin-draining lymph nodes contain dermis-derived CD103− dendritic cells that constitutively produce retinoic acid and induce Foxp3+ regulatory T cells

Abstract

Small intestinal CD103 ؉ dendritic cells (DCs) have the selective ability to promote de novo generation of regulatory T cells via the production of retinoic acid (RA). Considering that aldehyde dehydrogenase (ALDH) activity controls the production of RA, we used a flow cytometrybased assay to measure ALDH activity at the single-cell level and to perform a comprehensive analysis of the RA-producing DC populations present in lymphoid and nonlymphoid mouse tissues. RA-producing DCs were primarily of the tissue-derived, migratory DC subtype and can be readily found in the skin and in the lungs as well as in their corresponding draining lymph nodes. The RA-producing skin-derived DCs were capable of triggering the generation of regulatory T cells, a finding demonstrating that the presence of RA-producing, tolerogenic DCs is not restricted to the intestinal tract as previously thought. Unexpectedly, the production of RA by skin DCs was restricted to CD103 ؊ DCs, indicating that CD103 expression does not constitute a "universal" marker for RA-producing mouse DCs. Finally, Toll-like receptor (TLR) triggering or the presence of a commensal microflora was not essential for the induction of ALDH activity in the discrete ALDH ؉ DC subsets that characterize tissues constituting environmental interfaces. (Blood. 2010;115: 1958-1968 IntroductionThe vitamin A metabolite retinoic acid (RA) is a lipophilic molecule that controls the activity of a constellation of genes via binding to nuclear receptors. 1 Vitamin A is derived from the diet, and the liver constitutes a large reservoir of vitamin A in the form of retinyl esters. Retinyl esters are hydrolyzed to retinol and released into the blood. Once retinol enters cells expressing appropriate enzymes, it is converted successively into retinal and RA. The first step of the conversion is catalyzed by alcohol dehydrogenases and by microsomal retinol dehydrogenases that are expressed by most cells, including dendritic cells (DCs). The second step consists of the oxidation of retinal into RA and is catalyzed by 3 aldehyde dehydrogenases (ALDHs), known as RALDH1, 2, and 3 and encoded by the Aldh1a1, -2, and -3 genes, respectively. RALDH expression is limited to certain cell types and, despite the widespread availability of retinol, only cells expressing one of the RALDHs can oxidize retinaldehyde to RA.Conventional DCs (cDCs) and plasmacytoid DCs (pDCs) reside throughout their life cycle in secondary lymphoid organs and are denoted as lymphoid tissue-resident DCs to distinguish them from tissue-derived, migratory DCs (mDCs). 2 cDCs express intermediate levels of major histocompatibility complex (MHC) class II molecules and high levels of CD11c (MHCII inter CD11c high ), whereas mDCs express high levels of MHC class II molecules and intermediate to high levels of CD11c (MHCII high CD11c inter to high ). Recently, DCs that are located in gut-associated lymphoid tissue (GALT) and express Aldh1a2 have gained considerable attention because of their ability to produce RA. On migration to me...

Significance of aldehyde dehydrogenase 1 expression in stromal cells of diffuse large B-cell lymphoma

“…Recently, Guilliams et al found expression of ALDH1 in macrophages in intestinal lamina propria, but did not report on their function (18). To our knowledge, this is the first report on ALDH1 + macrophages in humans, but failed to show the clinical implication.…”

“…To search for the presence of CICs in DLBCL, the ALDH1 + Recently, ALDH1 expression has been reported in murine DCs derived from the gut (17), lung (5) and dermis (18). In humans, there have been no reports on ALDH1 expression in DCs.…”

“…To our knowledge, this is the first report on ALDH1 expression in human DCs. Murine gut and dermal ALDH1 + DCs induce regulatory T cells (18,19), and thus may inhibit antitumorigenic immunity. The present study revealed that DLBCL patients with ALDH1 + DCs were associated with an unfavorable prognosis compared to those without, suggesting that human ALDH1 + DCs may induce regulatory T cells and inhibit antitumorigenic immunity.…”

From skin dendritic cells to a simplified classification of human and mouse dendritic cell subsets

“…pDC accumulation in lymphoid tissues, mucosa and organs occurs during several human pathologies, particularly in LN of patients affected by sarcoidosis, Mycobacterium tuberculosis infection [16], Kikuchi's disease [17], and in the skin of patients affected by psoriasis [18,19], systemic lupus erythematosus (SLE) [20] and lichen planus [21,22]. pDC accumulation has also been observed in brain lesions of patients with multiple sclerosis [23], in the salivary glands of patients with Sjogren's syndrome [24] and the synovia or inflamed muscle tissue/skin of people afflicted with rheumatoid arthritis [25,26] or dermatomyositis [27,28], respectively. pDC are over-represented in the blood of…”

“…Considering that RALDH expression is the only rate-limiting factor for RA production, Guilliams et al [27] used a flow cytometry-based assay to measure RALDH activity at the single-cell level and comprehensively analyzed RA-producing mouse DC populations. RA-producing DC were readily found in the skin and in the lungs, as well as the draining LN of these organs.…”