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Incomplete Depletion and Rapid Regeneration of Foxp3⁺ Regulatory T Cells Following Anti-CD25 Treatment in Malaria-Infected Mice¹

Kevin N. Couper^*, Daniel G. Blount^*, J. Brian de Souza^*,, Isabelle Suffia, Yasmine Belkaid and Eleanor M. Riley^2,*

^* Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, U.K.; Department of Immunology and Molecular Pathology, University College London Medical School, London, U.K.; and Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892

Investigation of the role of regulatory T cells (Treg) in model systems is facilitated by their depletion using anti-CD25 Abs, but there has been considerable debate about the effectiveness of this strategy. In this study, we have compared the depletion and repopulation of CD4⁺CD25⁺Foxp3⁺ Treg in uninfected and malaria-infected mice using 7D4 and/or PC61 anti-CD25 Abs. We find that numbers and percentages of CD25^high cells, but not Foxp3⁺ cells, are transiently reduced after 7D4 treatment, whereas treatment with PC61 alone or in combination with 7D4 (7D4 plus PC61) reduces but does not eliminate Foxp3⁺ cells for up to 2 wk. Importantly, all protocols fail to eliminate significant populations of CD25^–Foxp3⁺ or CD25^lowFoxp3⁺ cells, which retain potent regulatory capacity. By adoptive transfer we show that repopulation of the spleen by CD25^highFoxp3⁺ cells results from the re-expression of CD25 on peripheral populations of CD25^–Foxp3⁺ but not from the conversion of peripheral Foxp3^– cells. CD25^highFoxp3⁺ repopulation occurs more rapidly in 7D4-treated mice than in 7D4 plus PC61-treated mice, reflecting ongoing clearance of emergent CD25⁺Foxp3⁺ cells by persistent PC61 Ab. However, in 7D4 plus PC61-treated mice undergoing acute malaria infection, repopulation of the spleen by CD25⁺Foxp3⁺ cells occurs extremely rapidly, with malaria infection driving proliferation and CD25 expression in peripheral CD4⁺CD25^–Foxp3⁺ cells and/or conversion of CD4⁺CD25^–Foxp3^– cells. Finally, we reveal an essential role for IL-2 for the re-expression of CD25 by Foxp3⁺ cells after anti-CD25 treatment and observe that TGF- is required, in the absence of CD25 and IL-2, to maintain splenic Foxp3⁺ cell numbers and a normal ratio of Treg:non-Treg cells.

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 study was funded by Wellcome Trust Grant 074538.

² Address correspondence and reprint requests to Dr. Eleanor Riley, London School of Hygiene and Tropical Medicine, Department of Infectious and Tropical Disease, Keppel Street, London, WC1E 7HT U.K. E-mail address: eleanor.riley{at}lshtm.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T cell; Teff, T effector cell.

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