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Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses

Abstract

The intestinal immune system must elicit robust immunity against harmful pathogens but must also restrain immune responses directed against commensal microbes and dietary antigens. The mechanisms that maintain this dichotomy are poorly understood. Here we describe a population of CD11b+F4/80+CD11c macrophages in the lamina propria that expressed several anti-inflammatory molecules, including interleukin 10 (IL-10), but little or no proinflammatory cytokines, even after stimulation with Toll-like receptor ligands. These macrophages induced, by a mechanism dependent on IL-10, retinoic acid and exogenous transforming growth factor-β, the differentiation of Foxp3+ regulatory T cells. In contrast, lamina propria CD11b+ dendritic cells elicited IL-17 production. This IL-17 production was suppressed by lamina propria macrophages, indicating that a dynamic interaction between these subsets may influence the balance between immune activation and tolerance.

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Figure 1: Phenotype, morphology and microenvironmental location of lamina propria macrophages.
Figure 2: Lamina propria macrophages have an anti-inflammatory gene expression 'signature'.
Figure 3: Lamina propria macrophages spontaneously secrete IL-10 and are hyporesponsive to TLR stimulation.
Figure 4: IL-10 derived from lamina propria macrophages inhibits the TH1 polarization of CD4+ T cells.
Figure 5: Induction of Foxp3+ Treg cells by lamina propria macrophages but not by DCs.
Figure 6: OT-II T cell cytokine production induced by lamina propria macrophages and DCs.
Figure 7: Intestinal DC subsets differentially generate IL-17-producing T cells.

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Acknowledgements

We thank M. Hulsey and S. Aguilar Mertens for assistance with cell sorting; T. Querec for assistance with gene array data analysis; R. Mittler (Emory University School of Medicine) for recombinant Flt3 ligand; A. Garcia for electron microscopy; M. Heffernan, S. Pai Kasturi and N. Murthy for synthesis of clodronate liposomes; W. Cao for genotyping CD11cDTR mice; and R. Ahmed (Emory University School of Medicine) and A. Sharpe (Harvard Medical School) for PD-L1 deficient mice. Supported by the National Institutes of Health (AI0564499, AI048638, AI05726601, DK057665, AI057157 and AI-50019 to B.P.; and DK007771-06A1 (Pathobiology of Mucosal/Epithelial Disease) to T.L.D.) and the Crohn's and Colitis Foundation of America (T.L.D.).

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T.L.D. and B.P. designed the experiments; T.L.D. did the experiments; Y.W., S.R.P. and I.R.W. did the immunohistology; and T.L.D. and B.P. wrote the manuscript.

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Correspondence to Bali Pulendran.

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Denning, T., Wang, Yc., Patel, S. et al. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses. Nat Immunol 8, 1086–1094 (2007). https://doi.org/10.1038/ni1511

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