Transient attenuated Foxp3 expression on CD4⁺ T cells treated with 7D4 mAb contributes to the control of parasite burden in DBA / 2 mice infected with lethal Plasmodium chabaudi chabaudi AS

Abstract

CD4(+) CD25(+) regulatory T (Treg) cells expressing Foxp3(+) play a critical role in maintaining immune homoeostasis and controlling excessive immune responses. However, controversy about the immunoregulatory role of Treg cells exists in malaria studies. Given the role of maintenance of Foxp3 expression in Treg cells' activities, we investigated whether anti-CD25 mAb (7D4 clone) treatment affects Foxp3 expression in CD4(+) T cells in DBA/2 mice infected with Plasmodium chabaudi chabaudi AS (P. c. chabaudi AS). We found that DBA/2 mice succumbed to P. c. chabaudi AS infection, which was accompanied by increased expression of Foxp3 in CD4(+) T cells at the peak parasitemia. In contrast, Foxp3 expression was impaired in CD25-depleted mice with 7D4 mAb treatment, leading to delayed parasitemia and extended survival of infected mice. Production of IFN-γ, TNF-α and IL-6, as well as NO was significantly enhanced in CD25-depleted mice. The majority of CD4(+) CTLA-4(+) cells expressed high levels of Foxp3 (Foxp3(hi) cells) in control mice with P. c. chabaudi AS infection. However, the number of CD4(+) Foxp3(hi) CTLA-4(+) cells was reduced in CD25-depleted mice. Together, these data suggest that CD4(+) Foxp3(hi) CTLA-4(+) cells may be involved in regulating the intensity of pro-inflammatory responses via CTLA-4.