Suppression of CD4⁺Effector Responses by Naturally Occurring CD4⁺CD25⁺Foxp3⁺Regulatory T Cells Contributes to Experimental Cerebral Malaria

Abstract

The role of naturally occurring CD4؉ CD25 ؉ Foxp3 ؉ regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4 ؉ T cells in an attenuated model of Plasmodium berghei ANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6) P. berghei ANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4 ؉ T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4؉ T cell response to P. berghei ANKA infection in vivo in both CM-susceptible (B6) and CM-resistant (B6-CD4 ؊/؊ ) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional during P. berghei ANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.

The IL-33/ST2 Pathway in Cerebral Malaria

“…Those cytokines increase the permeability of the blood–brain barrier (BBB) and promote T cells and inflammatory monocytes infiltration which results in brain œdema, axonal damage, and myelin loss [ 3 , 4 ]. Experimental mouse models which utilize Plamodium berghei ANKA ( Pb A) infection of C57BL/6 mice have shown that pathogenic CD4 + and CD8 + T cells, detected in the brain at the onset of neurological symptoms, play a role both at local and systemic levels by contributing to the high levels of TNF-α, IFN-γ and CXCL10 in circulation [ 5 , 6 , 7 ]. The development of CM is associated with recruitment in the brain of CD8 + T cells identified as one of the critical effector cell types mediating human cerebral malaria (HCM) and experimental cerebral malaria (ECM) [ 5 , 8 ].…”