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

Abstract

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 (TH1) cells which activates the macrophages. IL-12 also caused some TH1 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 (TH1-specific T box transcription factor) or IFN-γ prevented postoperative ileus. CCR9+ TH1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a TH1 immune-mediated disease and identify potential targets for disease monitoring and therapy.

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Figure 1: T helper memory cells are essential for ileus.
Figure 2: Intestinal manipulation induces TH1 responses that are essential for postoperative ileus.
Figure 3: TH1 memory cells migrate from manipulated to unmanipulated intestinal segments.
Figure 4: Pharmacological inhibition of memory TH1 cell activation and migration protects mice from postoperative ileus.
Figure 5: Intestinal DCs produce IL-12 that stimulates TH1 memory cells.

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Acknowledgements

We thank M. Lysson for technical assistance, S. Hegenbarth for producing monoclonal antibodies and M. Forst for animal maintenance, and we acknowledge the support of the Central Animal Facilities and the Flow Cytometry Core Facility at the Institutes for Molecular Medicine and Experimental Immunology. D.R.E., S.W., J.C.K., A.K. and C.K. were supported by the Cooperative Clinical Research Center KFO115 of the Deutsche Forschungsgemeinschaft (Grants Ka1270/9-1/2 and Ku1063/4-1).

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D.R.E., A.K., M.S., L.F. and J.M. performed the experiments. D.R.E., A.K., J.C.K. and C.K. designed the study and wrote the manuscript. J.C.K. supervised the surgical part and C.K. supervised the immunological part of the study. S.W., A.H. and P.A.K. provided crucial ideas. T.S., B.S. and A.L. provided crucial reagents. All authors discussed and interpreted results.

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Correspondence to Jörg C Kalff or Christian Kurts.

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The authors declare no competing financial interests.

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Engel, D., Koscielny, A., Wehner, S. et al. T helper type 1 memory cells disseminate postoperative ileus over the entire intestinal tract. Nat Med 16, 1407–1413 (2010). https://doi.org/10.1038/nm.2255

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