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

Abstract

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).