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CTLA-4 and CD4⁺CD25⁺ Regulatory T Cells Inhibit Protective Immunity to Filarial Parasites In Vivo¹

Matthew D. Taylor^2,*, Anjanette Harris, Simon A. Babayan, Odile Bain, Abigail Culshaw, Judith E. Allen and Rick M. Maizels

^* Institute of Immunology and Infection Research, University of Edinburgh, United Kingdom; and Parasitologie Comparée et Modèles Expérimentaux, Muséum National d’Histoire Naturelle, Paris, France

The T cell coinhibitory receptor CTLA-4 has been implicated in the down-regulation of T cell function that is a quintessential feature of chronic human filarial infections. In a laboratory model of filariasis, Litomosoides sigmodontis infection of susceptible BALB/c mice, we have previously shown that susceptibility is linked both to a CD4⁺CD25⁺ regulatory T (Treg) cell response, and to the development of hyporesponsive CD4⁺ T cells at the infection site, the pleural cavity. We now provide evidence that L. sigmodontis infection drives the proliferation and activation of CD4⁺Foxp3⁺ Treg cells in vivo, demonstrated by increased uptake of BrdU and increased expression of CTLA-4, Foxp3, GITR, and CD25 compared with naive controls. The greatest increases in CTLA-4 expression were, however, seen in the CD4⁺Foxp3^– effector T cell population which contained 78% of all CD4⁺CTLA-4⁺ cells in the pleural cavity. Depletion of CD25⁺ cells from the pleural CD4⁺ T cell population did not increase their Ag-specific proliferative response in vitro, suggesting that their hyporesponsive phenotype is not directly mediated by CD4⁺CD25⁺ Treg cells. Once infection had established, killing of adult parasites could be enhanced by neutralization of CTLA-4 in vivo, but only if performed in combination with the depletion of CD25⁺ Treg cells. This work suggests that during filarial infection CTLA-4 coinhibition and CD4⁺CD25⁺ Treg cells form complementary components of immune regulation that inhibit protective immunity in vivo.

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 the Medical Research Council (G9901118) and the European Commission (ICA4-CT-1999-10002). R.M.M. was supported by a Wellcome Trust Programme Grant and M.D.T. was partially supported by a Wellcome Trust VIP Award.

² Address correspondence and reprint requests to Dr. Matthew D. Taylor, Institute of Immunology and Infection Research, Ashworth Laboratories, West Mains Road, University of Edinburgh, Edinburgh, U.K. E-mail address: Matthew.Taylor{at}ed.ac.uk

³ Abbreviations used in this paper: DC, dendritic cell; Treg, regulatory T; Teff, effector T; Mf, microfilariae; LsAg, Litomosoides sigmodontis whole worm Ag; tLN, thoracic lymph node; PleC, pleural cavity cell; FC, flow cytometry; GLM, generalized linear model; pleCD4⁺, pleural cavity CD4⁺.

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