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 (Treg) 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+ Treg specifically. To study the function of Treg in the genesis of CM, we used depletion of Treg 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+ Treg by diphtheria toxin injection, and also their specific detection and purification during an ongoing infection. Using depletion of Treg mice, we found only a small increase in the absolute numbers of Foxp3+ Treg during PbA infection and, consequently, the ratio of Treg to T effector cells (Teff) decreased due to the rapid expansion of Teff. Although the latter sequester in the brains of infected mice, almost no Treg were found in the brains of infected mice. Furthermore, we demonstrate that depletion of Treg has no influence on sequestration of Teff and on the clinical outcome, and only minor influence on T cell activation. Using ex vivo analysis of purified Treg from either naive mice or PbA-infected mice, we found that both exhibit similar inhibitory capacity on Teff.

Role of IL‐10‐producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice

“…For example, it was reported that Treg cells induced in vivo by IL-2/anti-IL-2 complexes in P. berghei infected mice protected the mice from neurological disease [9]. A study by Steeg et al [11] showed that selective depletion of CD4 + Foxp3 + cells had no apparent effect on CM development in P. berghei infection. In this study, we also evaluate the role of CD4 + CD25 + Treg cells in regulation of CM development.…”

“…Several studies have investigated the role of Treg cells, defined either by CD4 + CD25 + or CD4 + Foxp3 + , in regulation of CM in murine malaria model, but inconsistent finding are reported [9,11,22,23]. To address this question, we performed experiment to determine the role of Treg cells, in parallel with Breg cells, in control of CM in P. berghei infected mice.…”

“…The levels of anti-inflammatory cytokines such as IL-10 and TGF-β have been shown to be inversely associated with the occurrence of CM in murine malaria [7,8]. However, no consensus has been reached concerning the role of regulatory T (Treg) cells in regulation of CM pathogenesis [9][10][11].…”

“…The levels of anti-inflammatory cytokines such as IL-10 and TGF-β have been shown to be inversely associated with the occurrence of CM in murine malaria [7,8]. However, no consensus has been reached concerning the role of regulatory T (Treg) cells in regulation of CM pathogenesis [9][10][11].B cells have been traditionally considered antibody-producing cell and APC. Many studies in recent years showed the existence of a subset of B cells that exhibit the immune regulatory functions (reviewed in [12]).…”

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

“…Regulatory T cells can be beneficial or detrimental to the induction of ECM depending on the method and timing of regulatory T cell depletion and the genetic background of the host (17)(18)(19)(20)(21)(22)(23)(24). Th17 cells, which induce tissue inflammation and are capable of disrupting the blood brain barrier (25), do not appear to contribute to the pathogenesis of ECM (26).…”