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Regulatory T Cells: A Role in the Control of Helminth-Driven Intestinal Pathology and Worm Survival¹

Riccardo D'Elia^2,*, Jerzy M. Behnke, Janette E. Bradley and Kathryn J. Else^*

^* Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and The School of Biology, University of Nottingham, University Park, Nottingham, United Kingdom

The chronic nature of intestinal nematode infections suggests that these parasites have evolved sophisticated immunomodulatory strategies. The induction of regulatory responses during chronic helminth infections could be advantageous to the host by minimizing damage incurred by these organisms. Regulation of the host immune response to infection could however be exploited by parasites as a survival strategy. We have explored both these aspects using the murine model of whipworm infection, Trichuris muris. Of the three laboratory isolates of T. muris in use, two (the E (Edinburgh) and J (Japan, subcultured from E)) are readily expelled by C57BL/6 mice, whereas the third, the S isolate (Sobreda, isolated from wild mice in Portugal) survives for much longer. The existence of the T. muris isolates thus presents a powerful tool to explore the mechanisms underlying chronic infection in a single strain of mouse. In this study, we show that S isolate-infected mice have increased numbers of Foxp3⁺ T cells in the gut compared with mice infected with the E isolate. Treatment of mice infected with the S isolate with either anti-CD25 or anti-glucocorticoid-induced TNFR exacerbated intestinal pathology, and, in addition, mice treated with anti-glucocorticoid-induced TNFR were able to expel worms more rapidly, implying the release of local effector mechanisms from a regulatory influence. Thus, our data show for the first time that T regulatory cells protect the host from worm-driven intestinal pathology. In addition, our data reveal a subversion of this damage-limiting response by the S isolate to facilitate its own survival.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ R.D. is supported by a PhD Studentship from the Biotechnology and Biological Sciences Research Council and K.J.E. is supported by a grant from the Wellcome Trust (Grant 081120).

² Address correspondence and reprint requests to Dr. Riccardo D'Elia, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, United Kingdom. E-mail address: riccardo.d'elia{at}postgrad.manchester.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T; ccu, colonic crypt unit; MLN, mesenteric lymph node; p.i., postinfection; CBA, cytometric bead array; GLM, generalized linear model.