Publication Date:
2009-03-06
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Torchinsky, Miriam Beer -- Garaude, Johan -- Martin, Andrea P -- Blander, J Magarian -- AI073899/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Mar 5;458(7234):78-82. doi: 10.1038/nature07781.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunology Institute, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19262671" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Apoptosis
;
*Cell Differentiation
;
Citrobacter rodentium/*immunology/physiology
;
Dendritic Cells/immunology/metabolism
;
Immunity, Innate/*immunology
;
Interleukin-10/biosynthesis/immunology
;
Interleukin-17/*immunology/metabolism
;
Interleukin-23/immunology
;
Interleukin-6/biosynthesis
;
Ligands
;
Mice
;
Mice, Inbred C57BL
;
Phagocytosis
;
T-Lymphocytes, Helper-Inducer/*cytology/*immunology/metabolism
;
Toll-Like Receptors/immunology/metabolism
;
Transforming Growth Factor beta/immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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