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Expansion of Foxp3⁺ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi¹

Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom

Many helminths, including Brugia malayi, are able to establish long-lived infections in immunocompetent hosts. Growing evidence suggests that the immune system’s failure to eliminate parasites is at least partially due to the effects of regulatory T cells (Tregs). To test whether parasites may directly stimulate host regulatory activity, we infected mice with two key stages of B. malayi. Both mosquito-borne infective larvae and mature adults i.p. introduced were found to preferentially expand the proportion of CD25⁺Foxp3⁺ cells within the CD4⁺ T cell population. The induction of Foxp3 was accompanied by raised CD25, CD103, and CTLA-4 expression, and was shown to be an active process, which accompanied the introduction of live, but not dead parasites. CTLA-4 expression was also markedly higher on Foxp3^– cells, suggesting anergized effector populations. Peritoneal lavage CD4⁺CD25⁺ cells from infected mice showed similar suppressive activity in vitro to normal splenic "natural" Tregs. Both B. malayi larvae and adults were also able to induce Foxp3 expression in adoptively transferred DO11.10 T cells, demonstrating that filarial infection can influence the development of T cells specific to a third party Ag. In addition, we showed that induction was intact in IL-4R-deficient animals, in the absence of a Th2 or alternatively activated macrophage response. We conclude that filarial infections significantly skew the balance of the host immune system toward Treg expansion and activation, in a manner dependent on live parasites but independent of a concomitant Th2 response.

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 This work was supported by studentship support from the Medical Research Council (to H.J.McS.) and a Research Career Award (to M.D.T). Y.M.H., J.M., and R.M.M. are supported by a Wellcome Trust Programme Grant.

² Address correspondence and reprint requests to Dr. Rick M. Maizels, Institute of Immunology and Infection Research, University of Edinburgh, Ashworth Laboratories, West Mains Road, Edinburgh EH9 3JT, U.K. E-mail address: r.maizels{at}ed.ac.uk

³ Abbreviations used in this paper: BMDC, bone marrow-derived dendritic cell; Treg, regulatory T cell.