T helper type 1 memory cells disseminate postoperative ileus over the entire intestinal tract

• Published in: Nature medicine Vol. 16; no. 12; pp. 1407 - 1413
• Main Authors: Engel, Daniel R, Koscielny, Arne, Wehner, Sven, Maurer, Juliane, Schiwon, Marzena, Franken, Lars, Schumak, Beatrix, Limmer, Andreas, Sparwasser, Tim, Hirner, Andreas, Knolle, Percy A, Kalff, Jörg C, Kurts, Christian
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2010; Nature Publishing Group
• Subjects: 631/250/1619/554/1898/1272; 692/699/1503/1581; 692/700/565/1436/1983; 692/700/565/545; Animals; Biomedical and Life Sciences; Biomedicine; Blood; Cancer Research; Cell Movement - drug effects; Cellular biology; Cytokines; Dendritic Cells - secretion; Digestive system; Fingolimod Hydrochloride; Flow Cytometry; Gastrointestinal surgery; Gastrointestinal tract; Health aspects; Humans; Ileus - etiology; Ileus - immunology; Ileus - prevention & control; Immune system; Immunologic Memory - immunology; Immunosuppressive Agents - pharmacology; Infectious Diseases; Interferon-gamma - immunology; Interleukin-12 - secretion; Intestines; Lymphocytes; Macrophages - metabolism; Metabolic Diseases; Mice; Mice, Inbred C57BL; Molecular Medicine; Neurosciences; Obstructions; Postoperative Complications - immunology; Postoperative period; Propylene Glycols - pharmacology; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Statistics, Nonparametric; Surgical outcomes; T cells; Th1 Cells - immunology; Germany
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2255

One complication arising from gastrointestinal surgery is ileus, in which local manipulation of the intestine leads to dysmotility and paralysis of the entire intestine. Christian Kurts and his colleagues find that after surgery T helper type 1 memory cells are activated by intestinal dendritic cells via interleukin-12, and migration of memory T cells through the portal vein induces paralysis of unmanipulated sites. Inhibition of interleukin-12 or prevention of lymphocyte egress with FTY720 prevents ileus and suggests new targets for therapeutic intervention. Localized abdominal surgery can lead to disruption of motility in the entire gastrointestinal tract (postoperative ileus). Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how the macrophages are activated, especially those in unmanipulated intestinal areas. Here we show that intestinal surgery activates intestinal CD103 + CD11b + dendritic cells (DCs) to produce interleukin-12 (IL-12). This promotes interferon-γ (IFN-γ) secretion by CCR9 + memory T helper type 1 (T H 1) cells which activates the macrophages. IL-12 also caused some T H 1 cells to migrate from surgically manipulated sites through the bloodstream to unmanipulated intestinal areas where they induced ileus. Preventing T cell migration with the drug FTY720 or inhibition of IL-12, T-bet (T H 1-specific T box transcription factor) or IFN-γ prevented postoperative ileus. CCR9 + T H 1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a T H 1 immune-mediated disease and identify potential targets for disease monitoring and therapy.