Decline of FoxP3+ Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria

FoxP3+ regulatory CD4 T cells (T(regs)) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that T(regs) are induced by P. falciparum both in vivo and in vitro; however, the factors influencing T(reg) homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of T(regs) in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ T(regs) in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of T(regs) from peripheral blood was accompanied by reduced in vitro induction of T(regs) by parasite antigen and decreased expression of TNFR2 on T(regs) among children who had intense prior exposure to malaria. While T(reg) frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower T(reg) frequencies. These data demonstrate that chronic malaria exposure results in altered T(reg) homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations.