title: Decline of FoxP3+ Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria.
abstract: FoxP3+ regulatory CD4 T cells (Tregs) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs 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+ Tregs 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 Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg 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 Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Center for Biomedical Research, The Burnet Institute, Melbourne, Australia.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Boyle
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Jagannathan
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Lila A
authors.initials: LA
authors.lastname: Farrington
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Ijeoma
authors.initials: I
authors.lastname: Eccles-James
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Samuel
authors.initials: S
authors.lastname: Wamala
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Tara I
authors.initials: TI
authors.lastname: McIntyre
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Hilary M
authors.initials: HM
authors.lastname: Vance
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bowen
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Felistas
authors.initials: F
authors.lastname: Nankya
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Ann
authors.initials: A
authors.lastname: Auma
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Mayimuna
authors.initials: M
authors.lastname: Nalubega
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Esther
authors.initials: E
authors.lastname: Sikyomu
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Kate
authors.initials: K
authors.lastname: Naluwu
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: John
authors.initials: J
authors.lastname: Rek
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Agaba
authors.initials: A
authors.lastname: Katureebe
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Victor
authors.initials: V
authors.lastname: Bigira
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: James
authors.initials: J
authors.lastname: Kapisi
authors.affiliation: CDC, Atlanta, Georgia, United States of America.
authors.forename: Jordan
authors.initials: J
authors.lastname: Tappero
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Muhindo
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Bryan
authors.initials: B
authors.lastname: Greenhouse
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Arinaitwe
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Grant
authors.initials: G
authors.lastname: Dorsey
authors.affiliation: Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda.
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Feeney
mesh_terms: D002648:Child; D002675:Child, Preschool; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007223:Infant; D008288:Malaria / Q000276:immunology* / Q000469:parasitology; D016778:Malaria, Falciparum / Q000276:immunology*; D010963:Plasmodium falciparum / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D014454:Uganda / Q000453:epidemiology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors