Cited by 365Phagocytosis and Immune RegulationT-cell and B-cell ImmunologyPsoriasis: Treatment and Pathogenesis

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Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation

Torchinsky, Miriam Beer, Garaude, Johan, Martin, Andrea P., Blander, J. Magarian·2009·Nature

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Abstract

Adaptive immune responses rely on differentiation of CD4 T helper cells into subsets with distinct effector functions best suited for host defence against the invading pathogen. Interleukin (IL)-17-producing T helper cells (T(H)17) are a recently identified subset, separate from the T helper type 1 (T(H)1) and T helper type 2 (T(H)2) subsets. Synergy between the cytokines transforming growth factor-beta and IL-6 in vitro induces development of T(H)17 cells in mouse and human systems, whereas IL-23 supports expansion of these cells. However, it is not known which conditions in vivo would induce this combination of cytokines. Furthermore, it is enigmatic that a combination of pro-inflammatory and anti-inflammatory cytokines would be required to generate an effector T(H)17 response. Here we show that the relevant physiological stimulus triggering this combination of cytokines is the recognition and phagocytosis of infected apoptotic cells by dendritic cells. Phagocytosis of infected apoptotic cells uniquely triggers the combination of IL-6 and transforming growth factor-beta through recognition of pathogen-associated molecular patterns and phosphatidylserine exposed on apoptotic cells, respectively. Conversely, phagocytosis of apoptotic cells in the absence of microbial signals induces differentiation of the closely related regulatory T cells, which are important for controlling autoimmunity. Blocking apoptosis during infection of the mouse intestinal epithelium with the rodent pathogen Citrobacter rodentium, which models human infections with the attaching and effacing enteropathogenic and enterohaemorrhagic Escherichia coli, impairs the characteristic T(H)17 response in the lamina propria. Our results demonstrate that infected apoptotic cells are a critical component of the innate immune signals instructing T(H)17 differentiation, and point to pathogens particularly adept at triggering apoptosis that might preferentially induce T(H)17-mediated immunity. Because T(H)17 cells have been correlated with autoimmune diseases, investigation of the pathways of innate recognition of infected apoptotic cells might lead to improved understanding of the causative defects in autoimmunity.

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Authors: Torchinsky, M. B., Garaude, J., Martin, A. P., & Blander, J. M.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Corresponding author: Blander, J. Magarian
ORCID: Garaude, Johan
Blander, J. Magarian
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2009-03
Volume: 458
Issue: 7234
Pages: 78-82
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature07781
OpenAlex: W2009887653
Cited by: 364
References: 31
Citations by year: 2026: 3 · 2025: 17 · 2024: 10 · 2023: 13 · 2022: 19 · 2021: 17 · 2020: 12 · 2019: 10 · 2018: 11 · 2017: 23 · 2016: 14 · 2015: 14 · 2014: 24 · 2013: 26 · 2012: 38
FWCI: 21.56
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institute of Allergy and Infectious Diseases (R56AI073899, R01AI073899, AI073899)
National Institute of Diabetes and Digestive and Kidney Diseases (P01DK072201)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords: Th17 cell differentiation, apoptotic cell engulfment, dendritic cells, innate immune recognition, phosphatidylserine, pathogen-associated molecular patterns, interleukin-6, TGF-beta, regulatory T cells, autoimmunity, Citrobacter rodentium, intestinal lamina propria, enteropathogenic Escherichia coli
MeSH terms: Animals, Cell Differentiation, Dendritic Cells, T-Lymphocytes, Helper-Inducer, Immunity, Innate, Ligands, Mice, Inbred C57BL, Phagocytosis, Interleukin-6, Transforming Growth Factor beta, Interleukin-10, Apoptosis, Interleukin-17, Citrobacter rodentium, Toll-Like Receptors, Mice, Interleukin-23

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Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation

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