Recognition and removal of apoptotic cells by professional phagocytes, including dendritic cells and macrophages, preserves immune self-tolerance and prevents chronic inflammation and autoimmune pathologies1,2. The diverse array of phagocytes that reside within different tissues, combined with the necessarily prompt nature of apoptotic cell clearance, makes it difficult to study this process in situ. The full spectrum of functions executed by tissue-resident phagocytes in response to homeostatic apoptosis, therefore, remains unclear. Here we show that mouse apoptotic intestinal epithelial cells (IECs), which undergo continuous renewal to maintain optimal barrier and absorptive functions3, are not merely extruded to maintain homeostatic cell numbers4, but are also sampled by a single subset of dendritic cells and two macrophage subsets within a well-characterized network of phagocytes in the small intestinal lamina propria5,6. Characterization of the transcriptome within each subset before and after in situ sampling of apoptotic IECs revealed gene expression signatures unique to each phagocyte, including macrophage-specific lipid metabolism and amino acid catabolism, and a dendritic-cell-specific program of regulatory CD4+ T-cell activation. A common ‘suppression of inflammation’ signature was noted, although the specific genes and pathways involved varied amongst dendritic cells and macrophages, reflecting specialized functions. Apoptotic IECs were trafficked to mesenteric lymph nodes exclusively by the dendritic cell subset and served as critical determinants for the induction of tolerogenic regulatory CD4+ T-cell differentiation. Several of the genes that were differentially expressed by phagocytes bearing apoptotic IECs overlapped with susceptibility genes for inflammatory bowel disease7. Collectively, these findings provide new insights into the consequences of apoptotic cell sampling, advance our understanding of how homeostasis is maintained within the mucosa and set the stage for development of novel therapeutics to alleviate chronic inflammatory diseases such as inflammatory bowel disease.
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Gene Expression Omnibus
We are grateful to S. V. Chittur and M. Kuentzel, SUNY at the Albany Center for Functional Genomics. We thank M. Bogunovic at Pennsylvania State University, S. Jung at the Weizmann Institute of Science, Blander Laboratory members, J. Ochando and C. Bare at the Icahn School of Medicine Flow Cytometry Core, and M. A. Blander and S. J. Blander for discussions, help, and support. This work was supported by institutional seed funds to J.M.B. J.M.B. and her laboratory were supported by NIH grants AI095245, AI123284, DK072201, the Burroughs Wellcome Fund, and the Leukemia and Lymphoma Society. R.J.C. was supported by NIH training grants 2T32A1007605-11 and 5T32DK007792-12. G.Ba. was supported by the Crohn’s and Colitis Foundation of America (CCFA) Research Fellowship Award. B.M.H: NIAID contract HHSN272201000054C and U19 AI117873. J.C.: R01 DK092235, U01 DK62429, U01 DK062422, philanthropic SUCCESS, Sanford J. Grossman Charitable Trust. S.A.L. and G.C.F.: NIH 5P01DK072201-09 and 5R01CA161373-04, CCFA 330239, and SUCCESS. G.Bo.: Jenna and Paul Segal grant.
Extended data figures
This file contains a glossary of gene names in alphabetical order.
About this article
Nature Immunology (2017)