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Memory TH2 cells induce alternatively activated macrophages to mediate protection against nematode parasites

Nature Medicine volume 12, pages 955–960 (2006)Cite this article

Abstract

Although primary and memory responses against bacteria and viruses have been studied extensively, T helper type 2 (TH2) effector mechanisms leading to host protection against helminthic parasites remain elusive1. Examination of the intestinal epithelial submucosa of mice after primary and secondary infections by a natural gastrointestinal parasite revealed a distinct immune-cell infiltrate after challenge, featuring interleukin-4–expressing memory CD4+ T cells that induced IL-4 receptorhi (IL-4Rhi) CD206+ alternatively activated macrophages2. In turn, these alternatively activated macrophages (AAMacs) functioned as important effector cells of the protective memory response contributing to parasite elimination, demonstrating a previously unknown mechanism for host protection against intestinal helminths.

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Figure 1: CD4+ T cell–dependent protective mechanisms occur at early stages after Hp challenge inoculation.
Figure 2: AAMac accumulation 4 d after H. polygyrus challenge is Stat6 dependent.
Figure 3: Macrophage depletion abrogates a protective TH2 memory response.
Figure 4: Arginase inhibition abrogates protective memory response to H. polygyrus.

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References

  1. Gause, W.C., Urban, J.F., Jr. & Stadecker, M.J. The immune response to parasitic helminths: insights from murine models. Trends Immunol. 24, 269–277 (2003).

    Article  CAS  Google Scholar 

  2. Noel, W., Raes, G., Hassanzadeh Ghassabeh, G., De Baetselier, P. & Beschin, A. Alternatively activated macrophages during parasite infections. Trends Parasitol. 20, 126–133 (2004).

    Article  CAS  Google Scholar 

  3. Mosmann, T.R., Cherwinski, B., Bond, M.W., Giedlin, M.A. & Coffman, R.L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).

    CAS  PubMed  Google Scholar 

  4. Maizels, R.M. et al. Helminth parasites—masters of regulation. Immunol. Rev. 201, 89–116 (2004).

    Article  CAS  Google Scholar 

  5. Zhu, Z. et al. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304, 1678–1682 (2004).

    Article  CAS  Google Scholar 

  6. Herbert, D.R. et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20, 623–635 (2004).

    Article  CAS  Google Scholar 

  7. Loke, P. et al. IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 3, 7 (2002).

    Article  Google Scholar 

  8. Urban, J.F., Jr., Katona, I.M., Paul, W.E. & Finkelman, F.D. Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc. Natl. Acad. Sci. USA 88, 5513–5517 (1991).

    Article  CAS  Google Scholar 

  9. Persson, L. A modified baermann apparatus for the recovery of infective nematode larvae from herbage and manure. Zentralbl. Veterinarmed. B. 21, 483–488 (1974).

    Article  CAS  Google Scholar 

  10. Morimoto, M. et al. Peripheral CD4 T cells rapidly accumulate at the host:parasite interface and express a polarized Th2 memory response in situ. J. Immunol. 172, 2424–2430 (2004).

    Article  CAS  Google Scholar 

  11. Liu, Z. et al. Requirements for the development of IL-4-producing T cells during intestinal nematode infections: what it takes to make a Th2 cell in vivo. Immunol. Rev. 201, 57–74 (2004).

    Article  CAS  Google Scholar 

  12. Voehringer, D., Reese, T.A., Huang, X., Shinkai, K. & Locksley, R.M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J. Exp. Med. 203, 1435–1446 (2006).

    Article  CAS  Google Scholar 

  13. Wynn, T.A. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat. Rev. Immunol. 4, 583–594 (2004).

    Article  CAS  Google Scholar 

  14. van Rooijen, N., Bakker, J. & Sanders, A. Transient suppression of macrophage functions by liposome-encapsulated drugs. Trends Biotechnol. 15, 178–185 (1997).

    Article  CAS  Google Scholar 

  15. Gobert, A.P. et al. Protective role of arginase in a mouse model of colitis. J. Immunol. 173, 2109–2117 (2004).

    Article  CAS  Google Scholar 

  16. Kuwano, K. et al. Oxidative stress in lung epithelial cells from patients with idiopathic interstitial pneumonias. Eur. Respir. J. 21, 232–240 (2003).

    Article  CAS  Google Scholar 

  17. Mei, B., Komuniecki, R. & Komuniecki, P.R. Localization of cytochrome oxidase and the 2-methyl branched-chain enoyl CoA reductase in muscle and hypodermis of Ascaris suum larvae and adults. J. Parasitol. 83, 760–763 (1997).

    Article  CAS  Google Scholar 

  18. Takamiya, S. et al. Molecular and functional properties of cytochrome c from adult Ascaris suum muscle. Mol. Biochem. Parasitol. 79, 61–70 (1996).

    Article  CAS  Google Scholar 

  19. Goerdt, S. et al. Alternative versus classical activation of macrophages. Pathobiology 67, 222–226 (1999).

    Article  CAS  Google Scholar 

  20. Mantovani, A., Sica, A. & Locati, M. Macrophage polarization comes of age. Immunity 23, 344–346 (2005).

    Article  CAS  Google Scholar 

  21. Hesse, M. et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J. Immunol. 167, 6533–6544 (2001).

    Article  CAS  Google Scholar 

  22. Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nat. Rev. Immunol. 5, 641–654 (2005).

    Article  CAS  Google Scholar 

  23. Madden, K.B. et al. Enteric nematodes induce stereotypic STAT6-dependent alterations in intestinal epithelial cell function. J. Immunol. 172, 5616–5621 (2004).

    Article  CAS  Google Scholar 

  24. Shea-Donohue, T. et al. The role of IL-4 in Heligmosomoides polygyrus-induced alterations in murine intestinal epithelial cell function. J. Immunol. 167, 2234–2239 (2001).

    Article  CAS  Google Scholar 

  25. Zhao, A. et al. Dependence of IL-4, IL-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves. J. Immunol. 171, 948–954 (2003).

    Article  CAS  Google Scholar 

  26. Cliffe, L.J. et al. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 308, 1463–1465 (2005).

    Article  CAS  Google Scholar 

  27. Ben-Smith, A., Lammas, D.A. & Behnke, J.M. The relative involvement of Th1 and Th2 associated immune responses in the expulsion of a primary infection of Heligmosomoides polygyrus in mice of differing response phenotype. J. Helminthol. 77, 133–146 (2003).

    Article  CAS  Google Scholar 

  28. Pennock, J.L. & Grencis, R.K. The mast cell and gut nematodes: damage and defence. Chem. Immunol. Allergy 90, 128–140 (2006).

    CAS  PubMed  Google Scholar 

  29. Nair, M.G. et al. Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells. Infect. Immun. 73, 385–394 (2005).

    Article  CAS  Google Scholar 

  30. Murakami, H., Liotta, L. & Star, R.A. IF-LCM: laser capture microdissection of immunofluorescently defined cells for mRNA analysis rapid communication. Kidney Int. 58, 1346–1353 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank F.D. Finkelman, S.J. Leibovich and E.J. Allenspach for critically reviewing this manuscript.

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Authors and Affiliations

  1. Department of Medicine, New Jersey Medical School, 185 S. Orange Avenue, Newark, 07103, New Jersey, USA

    Robert M Anthony, Farhang Alem, Hossein A Hamed, Cristina T Rozo & William C Gause

  2. Department of Microbiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, 20814, Maryland, USA

    Robert M Anthony & William C Gause

  3. US Department of Agriculture, Nutrient Requirements and Functions Laboratory, Beltsville Human Nutrition Research Center, 10300 Baltimore Avenue, Bldg 307-C CARC-EAST, Beltsville, 20705, Maryland, USA

    Joseph F Urban Jr

  4. Laboratoire de Chimie et Biochimie Pharmacologiques, Unité Mixte de Recherche 8601, Centre National de la Recherche Scientifique, Université René Descartes, Paris, France

    Jean-Luc Boucher

  5. Department of Molecular Cell Biology, Vrije Universiteit, VUMC, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands

    Nico Van Rooijen

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Correspondence to William C Gause.

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Supplementary information

Supplementary Fig. 1

The life cycle of H. polygyrus. (PDF 144 kb)

Supplementary Fig. 2

An inflammatory Th2 microenviroment develops around Hp larvae 4 days after challenge. (PDF 205 kb)

Supplementary Fig. 3

CD4+ T cells from Hp primed and drug cured mice can transfer protection to wild type, but not stat6−/− mice. (PDF 1263 kb)

Supplementary Fig. 4

Collagen is deposited around the parasite at later stages of a challenge infection and is associated with the Th2 inflammatory response. (PDF 189 kb)

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Anthony, R., Urban, J., Alem, F. et al. Memory TH2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat Med 12, 955–960 (2006). https://doi.org/10.1038/nm1451

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