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

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.

Blanc AL ，Keswani T ，Gorgette O ，Bandeira A ，Malissen B ，Cazenave PA ，Pied S ... -  《-》

Plasmodium berghei ANKA infection increases Foxp3, IL-10 and IL-2 in CXCL-10 deficient C57BL/6 mice.

Sarfo BY ，Wilson NO ，Bond VC ，Stiles JK ... -  《-》

CD4+ CD25+ regulatory T cells suppress CD4+ T-cell function and inhibit the development of Plasmodium berghei-specific TH1 responses involved in cerebral malaria pathogenesis.

Nie CQ ，Bernard NJ ，Schofield L ，Hansen DS ... -  《-》

Regulatory CD4+ CD25+ Foxp3+ T cells expand during experimental Plasmodium infection but do not prevent cerebral malaria.

Vigário AM ，Gorgette O ，Dujardin HC ，Cruz T ，Cazenave PA ，Six A ，Bandeira A ，Pied S ... -  《INTERNATIONAL JOURNAL FOR PARASITOLOGY》

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

Cerebral malaria (CM) is a neurological syndrome often occurring in severe malaria. Although CM is known as an immunopathology in brain tissue mediated by excessive proinflammatory cytokines, the immunoregulatory mechanism is poorly understood. Here, we investigated the role of IL-10-producing regulatory B (Breg) cells in modulating CM development in a murine model of Plasmodium berghei ANKA infection. We observed that blood-stage P. berghei induced expansion of IL-10-producing Breg cells in C57BL/6 mice. Adoptive transfer of IL-10(+) Breg cells to P. berghei infected mice significantly reduced the accumulation of NK and CD8(+) T cells and hemorrhage in brain tissue, and improved the survival of the mice compared with control groups, although parasitemia levels were not altered. Treatment of Breg-cell recipient mice with anti-IL-10 receptor mAb blocked the protective effect of Breg cells. Adoptive transfer of CD4(+) CD25(+) Treg cells failed to prevent CM in infected mice. Spleen cells from Breg-cell recipient mice produced increased levels of IL-10 in vitro. Cell co-culture showed that purified IL-10(+) B cells, but not IL-10(-) B cells, promoted IL-10 production by CD4(+) T cells. These results demonstrate that IL-10-producing Breg cells may represent an important mechanism for controlling the immunopathology and prevention of CM associated with P. berghei infection.

Liu Y ，Chen Y ，Li Z ，Han Y ，Sun Y ，Wang Q ，Liu B ，Su Z ... -  《-》