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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.

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