1. Immunology Institute, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA

Correspondence to: J. Magarian Blander¹ Correspondence and requests for materials should be addressed to J.M.B. (Email: julie.blander@mssm.edu).

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_H17) are a recently identified subset, separate from the T helper type 1 (T_H1) and T helper type 2 (T_H2) subsets¹. Synergy between the cytokines transforming growth factor- and IL-6 in vitro induces development of T_H17 cells in mouse^{1, 2, 3, 4, 5} and human⁶ systems, whereas IL-23 supports expansion of these cells^{2, 4, 5}. 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_H17 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- through recognition of pathogen-associated molecular patterns⁷ and phosphatidylserine exposed on apoptotic cells⁸, 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 autoimmunity⁹. Blocking apoptosis during infection of the mouse intestinal epithelium with the rodent pathogen Citrobacter rodentium¹⁰, which models human infections with the attaching and effacing enteropathogenic and enterohaemorrhagic Escherichia coli, impairs the characteristic T_H17 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 T_H17-mediated immunity. Because T_H17 cells have been correlated with autoimmune diseases¹, investigation of the pathways of innate recognition of infected apoptotic cells might lead to improved understanding of the causative defects in autoimmunity.

1. Immunology Institute, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA

Correspondence to: J. Magarian Blander¹ Correspondence and requests for materials should be addressed to J.M.B. (Email: julie.blander@mssm.edu).

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.