Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Kalff, J.C., Schraut, W.H., Billiar, T.R., Simmons, R.L. & Bauer, A.J. Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents. Gastroenterology 118, 316–327 (2000).

    Article  CAS  Google Scholar 

  2. Bauer, A.J., Schwarz, N.T., Moore, B.A., Turler, A. & Kalff, J.C. Ileus in critical illness: mechanisms and management. Curr. Opin. Crit. Care 8, 152–157 (2002).

    Article  Google Scholar 

  3. Schwarz, N.T. et al. Selective jejunal manipulation causes postoperative pan-enteric inflammation and dysmotility. Gastroenterology 126, 159–169 (2004).

    Article  CAS  Google Scholar 

  4. Wehner, S. et al. Inhibition of macrophage function prevents intestinal inflammation and postoperative ileus in rodents. Gut 56, 176–185 (2007).

    Article  CAS  Google Scholar 

  5. Bauer, A.J. Mentation on the immunological modulation of gastrointestinal motility. Neurogastroenterol. Motil. 20 (Suppl 1), 81–90 (2008).

    Article  CAS  Google Scholar 

  6. Goldstein, J.L. et al. Inpatient economic burden of postoperative ileus associated with abdominal surgery in the United States. P&T Journal 32, 82–90 (2007).

    Google Scholar 

  7. Iyer, S., Saunders, W.B. & Stemkowski, S. Economic burden of postoperative ileus associated with colectomy in the United States. J. Manag. Care Pharm. 15, 485–494 (2009).

    PubMed  Google Scholar 

  8. Barquist, E. et al. Neuronal pathways involved in abdominal surgery–induced gastric ileus in rats. Am. J. Physiol. 270, R888–R894 (1996).

    CAS  PubMed  Google Scholar 

  9. Barada, K.A. et al. Localized colonic inflammation increases cytokine levels in distant small intestinal segments in the rat. Life Sci. 79, 2032–2042 (2006).

    Article  CAS  Google Scholar 

  10. de Jonge, W.J. et al. Postoperative ileus is maintained by intestinal immune infiltrates that activate inhibitory neural pathways in mice. Gastroenterology 125, 1137–1147 (2003).

    Article  Google Scholar 

  11. Türler, A. et al. Leukocyte-derived inducible nitric oxide synthase mediates murine postoperative ileus. Ann. Surg. 244, 220–229 (2006).

    Article  Google Scholar 

  12. Wehner, S. et al. Inhibition of p38 mitogen–activated protein kinase pathway as prophylaxis of postoperative ileus in mice. Gastroenterology 136, 619–629 (2009).

    Article  CAS  Google Scholar 

  13. Dardalhon, V., Korn, T., Kuchroo, V.K. & Anderson, A.C. Role of TH1 and TH17 cells in organ-specific autoimmunity. J. Autoimmun. 31, 252–256 (2008).

    Article  CAS  Google Scholar 

  14. Szabo, S.J. et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science 295, 338–342 (2002).

    Article  CAS  Google Scholar 

  15. Neurath, M.F., Finotto, S. & Glimcher, L.H. The role of TH1/TH2 polarization in mucosal immunity. Nat. Med. 8, 567–573 (2002).

    Article  CAS  Google Scholar 

  16. Bouma, G. & Strober, W. The immunological and genetic basis of inflammatory bowel disease. Nat. Rev. Immunol. 3, 521–533 (2003).

    Article  CAS  Google Scholar 

  17. Strober, W., Fuss, I. & Mannon, P. The fundamental basis of inflammatory bowel disease. J. Clin. Invest. 117, 514–521 (2007).

    Article  CAS  Google Scholar 

  18. Gutcher, I. & Becher, B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J. Clin. Invest. 117, 1119–1127 (2007).

    Article  CAS  Google Scholar 

  19. Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    Article  CAS  Google Scholar 

  20. Bettelli, E., Oukka, M. & Kuchroo, V.K. TH-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8, 345–350 (2007).

    Article  CAS  Google Scholar 

  21. Paust, H.J. et al. The IL-23/TH17 axis contributes to renal injury in experimental glomerulonephritis. J. Am. Soc. Nephrol. 20, 969–979 (2009).

    Article  CAS  Google Scholar 

  22. Yen, D. et al. IL-23 is essential for T cell–mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    Article  CAS  Google Scholar 

  23. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  Google Scholar 

  24. Leppkes, M. et al. RORγ-expressing TH17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136, 257–267 (2009).

    Article  CAS  Google Scholar 

  25. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  Google Scholar 

  26. Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009).

    Article  CAS  Google Scholar 

  27. Wakim, L.M., Waithman, J., van Rooijen, N., Heath, W.R. & Carbone, F.R. Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science 319, 198–202 (2008).

    Article  CAS  Google Scholar 

  28. Heymann, F. et al. Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury. J. Clin. Invest. 119, 1286–1297 (2009).

    Article  CAS  Google Scholar 

  29. Coombes, J.L. & Powrie, F. Dendritic cells in intestinal immune regulation. Nat. Rev. Immunol. 8, 435–446 (2008).

    Article  CAS  Google Scholar 

  30. Rescigno, M. & Di Sabatino, A. Dendritic cells in intestinal homeostasis and disease. J. Clin. Invest. 119, 2441–2450 (2009).

    Article  CAS  Google Scholar 

  31. Varol, C., Zigmond, E. & Jung, S. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria. Nat. Rev. Immunol. 10, 415–426 (2010).

    Article  CAS  Google Scholar 

  32. Kalff, J.C., Schraut, W.H., Simmons, R.L. & Bauer, A.J. Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus. Ann. Surg. 228, 652–663 (1998).

    Article  CAS  Google Scholar 

  33. Lahl, K. et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57–63 (2007).

    Article  CAS  Google Scholar 

  34. Schulz, E.G., Mariani, L., Radbruch, A. & Hofer, T. Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-γ and interleukin-12. Immunity 30, 673–683 (2009).

    Article  CAS  Google Scholar 

  35. Mora, J.R. et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003).

    Article  CAS  Google Scholar 

  36. Cyster, J.G. Chemokines, sphingosine-1-phosphate and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127–159 (2005).

    Article  CAS  Google Scholar 

  37. Tomita, T. et al. Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice. Inflamm. Bowel Dis. 14, 1630–1640 (2008).

    Article  Google Scholar 

  38. Kunisawa, J. et al. Sphingosine 1-phosphate dependence in the regulation of lymphocyte trafficking to the gut epithelium. J. Exp. Med. 204, 2335–2348 (2007).

    Article  CAS  Google Scholar 

  39. Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002).

    Article  CAS  Google Scholar 

  40. de Jonge, W.J. et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat. Immunol. 6, 844–851 (2005).

    Article  CAS  Google Scholar 

  41. Schaefer, N. et al. Role of resident macrophages in the immunologic response and smooth muscle dysfunction during acute allograft rejection after intestinal transplantation. Transpl. Int. 21, 778–791 (2008).

    Article  CAS  Google Scholar 

  42. Boeckxstaens, G.E. & de Jonge, W.J. Neuroimmune mechanisms in postoperative ileus. Gut 58, 1300–1311 (2009).

    Article  CAS  Google Scholar 

  43. Ahern, P.P., Izcue, A., Maloy, K.J. & Powrie, F. The interleukin-23 axis in intestinal inflammation. Immunol. Rev. 226, 147–159 (2008).

    Article  Google Scholar 

  44. Weigmann, B. et al. The transcription factor NFATc2 controls IL-6–dependent T cell activation in experimental colitis. J. Exp. Med. 205, 2099–2110 (2008).

    Article  CAS  Google Scholar 

  45. Ogawa, A., Andoh, A., Araki, Y., Bamba, T. & Fujiyama, Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin. Immunol. 110, 55–62 (2004).

    Article  CAS  Google Scholar 

  46. Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009).

    CAS  PubMed  Google Scholar 

  47. McGeachy, M.J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivo. Nat. Immunol. 10, 314–324 (2009).

    Article  CAS  Google Scholar 

  48. Hu, J. & August, A. Naive and innate memory phenotype CD4+ T cells have different requirements for active Itk for their development. J. Immunol. 180, 6544–6552 (2008).

    Article  CAS  Google Scholar 

  49. Johansson-Lindbom, B. et al. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 202, 1063–1073 (2005).

    Article  CAS  Google Scholar 

  50. Sun, C.M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 Treg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  Google Scholar 

  51. Coombes, J.L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid–dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    Article  CAS  Google Scholar 

  52. Denning, T.L., Wang, Y.C., Patel, S.R., Williams, I.R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses. Nat. Immunol. 8, 1086–1094 (2007).

    Article  CAS  Google Scholar 

  53. Uematsu, S. et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 9, 769–776 (2008).

    Article  CAS  Google Scholar 

  54. Mannon, P.J. et al. Anti–interleukin-12 antibody for active Crohn's disease. N. Engl. J. Med. 351, 2069–2079 (2004).

    Article  CAS  Google Scholar 

  55. Ludwig-Portugall, I., Hamilton-Williams, E.E., Gottschalk, C. & Kurts, C. Cutting edge: CD25+ regulatory T cells prevent expansion and induce apoptosis of B cells specific for tissue autoantigens. J. Immunol. 181, 4447–4451 (2008).

    Article  CAS  Google Scholar 

  56. Kalff, J.C., Schwarz, N.T., Walgenbach, K.J., Schraut, W.H. & Bauer, A.J. Leukocytes of the intestinal muscularis: their phenotype and isolation. J. Leukoc. Biol. 63, 683–691 (1998).

    Article  CAS  Google Scholar 

  57. Schaefer, N. et al. Resident macrophages are involved in intestinal transplantation-associated inflammation and motoric dysfunction of the graft muscularis. Am. J. Transplant. 7, 1062–1070 (2007).

    Article  CAS  Google Scholar 

  58. Wehner, S. et al. Measurement of gastrointestinal and colonic transit in mice. Nat. Protoc. published online, doi:10.1038/protex.2010.1158 (28 November 2010).

  59. Chirdo, F.G., Millington, O.R., Beacock-Sharp, H. & Mowat, A.M. Immunomodulatory dendritic cells in intestinal lamina propria. Eur. J. Immunol. 35, 1831–1840 (2005).

    Article  CAS  Google Scholar 

  60. Semmling, V. et al. Alternative cross-priming through CCL17-CCR4–mediated attraction of CTLs toward NKT cell-licensed DCs. Nat. Immunol. 11, 313–320 (2010).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding authors

Correspondence to Jörg C Kalff or Christian Kurts.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–7, Supplementary Table 1 and Supplementary Methods (PDF 1899 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2255

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing