Adaptive immune responses rely on differentiation of CD4 T helper cells into subsets with distinct effector functions best suited for host defense against the invading pathogen. Interleukin (IL)-17 producing T helper cells (TH17) are a recently identified subset, separate from the T helper type 1 (TH1) and T helper type 2 (TH2) subsets. T H17 cells are induced in vitro by the cytokines transforming growth factor-β (TGF-β) and IL-6. However, it is not known what 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 TH17 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 TGF-β 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 (T reg), which are important for controlling autoimmunity. Blocking apoptosis during infection of the intestinal epithelium with the rodent pathogen Citrobacter rodentium impairs the characteristic TH17 response in the lamina propria. Our results demonstrate that infected apoptotic cells are a critical component of the innate immune signals instructing T H17 differentiation, and point to pathogens particularly adept at triggering apoptosis that might preferentially induce TH17-mediated immunity.
|Advisor:||Blander, Julie M.|
|Commitee:||Green, Douglas R., Lira, Sergio A., Mayer, Lloyd, Moran, Thomas M.|
|School:||Mount Sinai School of Medicine of New York University|
|School Location:||United States -- New York|
|Source:||DAI-B 70/08, Dissertation Abstracts International|
|Subjects:||Cellular biology, Microbiology, Immunology|
|Keywords:||Apoptosis, Innate immunity, Phagocytosis, Regulatory T cells, T helper 17, Toll-like receptors|
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