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.