Minimal Differentiation of Classical Monocytes as They Survey Steady-State Tissues and Transport Antigen to Lymph Nodes

Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Immunity (Impact Factor: 21.56). 09/2013; 39(3). DOI: 10.1016/j.immuni.2013.08.007
Source: PubMed


It is thought that monocytes rapidly differentiate to macrophages or dendritic cells (DCs) upon leaving blood. Here we have shown that Ly-6C(+) monocytes constitutively trafficked into skin, lung, and lymph nodes (LNs). Entry was unaffected in gnotobiotic mice. Monocytes in resting lung and LN had similar gene expression profiles to blood monocytes but elevated transcripts of a limited number of genes including cyclo-oxygenase-2 (COX-2) and major histocompatibility complex class II (MHCII), induced by monocyte interaction with endothelium. Parabiosis, bromodoxyuridine (BrdU) pulse-chase analysis, and intranasal instillation of tracers indicated that instead of contributing to resident macrophages in the lung, recruited endogenous monocytes acquired antigen for carriage to draining LNs, a function redundant with DCs though differentiation to DCs did not occur. Thus, monocytes can enter steady-state nonlymphoid organs and recirculate to LNs without differentiation to macrophages or DCs, revising a long-held view that monocytes become tissue-resident macrophages by default.

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Available from: Claudia Jakubzick, Aug 27, 2015
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    • "The reduction of these cells in the spleen could be due to either maturation-induced cell death or migration, or a phenotypic alteration of the cells (Asselin-Paturel et al., 2005; Swirski et al., 2009). Although not quantified as a separate population here, the percentage of transitional Ly6C + MHCII + cells increased as expected because immune activation triggers the differentiation of Ly6C + MHCII − cells to Ly6C − MHCII + cells (Jakubzick et al., 2013). Cells within gate 2 displayed fewer changes with CpG but, a significant increase in the percentage of CD8 + cDC1s was detected (Fig 3). "
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    ABSTRACT: The role of antigen presenting cells (APCs) in the pathogenesis of autoimmune- and other inflammatory diseases is now better understood due to advances in multicolor flow cytometry, gene expression analysis of APC populations, and functional correlation of mouse to human APC populations. A simple but informative nomenclature of conventional and plasmacytoid dendritic cell subsets (cDC1, cDC2, pDC) and monocyte-derived populations incorporates these advances, but accurate subset identification is critical. Ambiguous gating schemes and alterations of cell surface markers in inflammatory condition can make comparing results between studies difficult. Both acute inflammation, such as TLR-ligand stimulation, and chronic inflammation as found in mouse models of autoimmunity can alter DC subset gating. Here, we address these issues using in vivo CpG stimulation as an example of acute inflammation and the non-obese diabetic (NOD) mouse as a model of chronic inflammation.We provide a flow cytometric antibody panel and gating scheme that differentiate 2 monocytic and 3 DC subsets in the spleen both at steady state and after CpG stimulation. Using this method, we observed differences in the composition of NOD DCs that have been previously reported, and newly identified increases in the number of NOD monocyte-derived DCs. Finally, we established a protocol for DC phosphoflow to measure the phosphorylation state of intracellular proteins, and use it to confirm functional differences in the identified subsets. Therefore, we present optimized methods for distinguishing monocytic and DC populations with and without inflammation and/or autoimmunity associated with NOD mice.
    Journal of immunological methods 09/2015; DOI:10.1016/j.jim.2015.08.015 · 1.82 Impact Factor
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    • "A recent review by Hussell and Bell provides an updated overview of the mechanisms of AM negative regulation [77]. Intestinal macrophages, as all tissue macrophages, also serve as antigen-presenting cells in triggering adaptive immune responses at the tissue level, and they can also contribute to T cell priming (through the so-called " tissue monocytes " that are able to recirculate to the lymph nodes [78]). In this regard, it is now believed that mucosal macrophages are able to transfer luminal antigens to neighboring CD103 + DCs through the gap junction channel protein connexin 43 [79]. "
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    • "APCs of the MPS appear to have commensurate increased expression of antigen presentation and co-stimulatory molecules, and are potent secretors of modulatory cytokines[12]. They are motile, and in other tissues have been shown to express chemokine receptors which facilitate their transit to draining lymph nodes, prime naïve T cells and establish a systemic immune response [13] [14] [15]. "
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