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Limited Role of CD4⁺Foxp3⁺ Regulatory T Cells in the Control of Experimental Cerebral Malaria¹

Christiane Steeg,^* Guido Adler,^* Tim Sparwasser, Bernhard Fleischer,^* and Thomas Jacobs^2*

*Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; and Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research, Twincore, Hanover, Germany

Cerebral malaria (CM) associated with Plasmodium berghei ANKA (PbA) infection is an accepted model of human CM. CM during PbA infection critically depends on sequestration of T cells into the brain. Several studies aimed to address the role of regulatory T cells (T_reg) in modulating this pathogenic T cell response. However, these studies are principally hampered due to the fact that until recently no reagents were available to deplete Foxp3⁺ T_reg specifically. To study the function of T_reg in the genesis of CM, we used depletion of T_reg mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin receptor-enhanced GFP fusion protein under the control of the foxp3 gene locus. These mice allow for a selective depletion of Foxp3⁺ T_reg by diphtheria toxin injection, and also their specific detection and purification during an ongoing infection. Using depletion of T_reg mice, we found only a small increase in the absolute numbers of Foxp3⁺ T_reg during PbA infection and, consequently, the ratio of T_reg to T effector cells (T_eff) decreased due to the rapid expansion of T_eff. Although the latter sequester in the brains of infected mice, almost no T_reg were found in the brains of infected mice. Furthermore, we demonstrate that depletion of T_reg has no influence on sequestration of T_eff and on the clinical outcome, and only minor influence on T cell activation. Using ex vivo analysis of purified T_reg from either naive mice or PbA-infected mice, we found that both exhibit similar inhibitory capacity on T_eff.

Correspondence: ² Address correspondence and reprint requests to Dr. Thomas Jacobs, Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany. E-mail address: tjacobs{at}bni-hamburg.de

¹ This work was supported by a grant of the Deutsche Forschungsgemeinschaft to T.J. (JA 1451).