IL-2 Contributes to Maintaining a Balance between CD4+Foxp3+ Regulatory T Cells and Effector CD4+ T Cells Required for Immune Control of Blood-Stage Malaria Infection

Abstract

To investigate the role of CD4+CD25+Foxp3+ regulatory T (Treg) cells in blood-stage malaria, we compared Plasmodium chabaudi AS infection in wild-type (WT) C57BL/6 and transgenic mice overexpressing the transcription factor Foxp3 (Foxp3Tg) and observed that Foxp3Tg mice experienced lethal infection and deficient malaria-specific immune responses. Adoptive transfer of total CD4+ T cells from Foxp3Tg mice or CD4+CD25+ T cells from WT mice to naive WT recipients confirmed that high numbers of Treg cells compromised immune control of malaria. Transfer of GFP+CD4+CD25+ T cells to naive WT recipients together with immunohistochemical staining of spleens from infected WT mice demonstrated that Foxp3+ Treg cells localized in the T cell area of the spleen. Determination of CD4+Foxp3+ Treg cell responses in the spleen of infected WT mice revealed a significant but transient increase in CD4+Foxp3+ Treg cells early in infection. This was followed by a significant and sustained decrease due to reduced proliferation and apoptosis of CD4+Foxp3+ Treg cells. Importantly, the kinetics of IL-2 secretion by effector CD4+Foxp3− T cells coincided with changes in CD4+Foxp3+ cells and the differentiation of CD4+T-bet+IFN-γ+ cells required for immune control of infection. Administration of the IL-2/anti–IL-2 mAb (clone JES6-1) complex to infected WT mice increased the severity of P. chabaudi AS infection and promoted expansion of Foxp3+ Treg cells. Collectively, these data demonstrate that the ability to control and eliminate P. chabaudi AS infection is due to a tight balance between natural Treg cells and effector CD4+ Th1 cells, a balance regulated in part by IL-2.