title: IFNγ/IL-10 co-producing cells dominate the CD4 response to malaria in highly exposed children.
abstract: Although evidence suggests that T cells are critical for immunity to malaria, reliable T cell correlates of exposure to and protection from malaria among children living in endemic areas are lacking. We used multiparameter flow cytometry to perform a detailed functional characterization of malaria-specific T cells in 78 four-year-old children enrolled in a longitudinal cohort study in Tororo, Uganda, a highly malaria-endemic region. More than 1800 episodes of malaria were observed in this cohort, with no cases of severe malaria. We quantified production of IFNγ, TNFα, and IL-10 (alone or in combination) by malaria-specific T cells, and analyzed the relationship of this response to past and future malaria incidence. CD4(+) T cell responses were measurable in nearly all children, with the majority of children having CD4(+) T cells producing both IFNγ and IL-10 in response to malaria-infected red blood cells. Frequencies of IFNγ/IL10 co-producing CD4(+) T cells, which express the Th1 transcription factor T-bet, were significantly higher in children with ≥2 prior episodes/year compared to children with <2 episodes/year (P<0.001) and inversely correlated with duration since malaria (Rho = -0.39, P<0.001). Notably, frequencies of IFNγ/IL10 co-producing cells were not associated with protection from future malaria after controlling for prior malaria incidence. In contrast, children with <2 prior episodes/year were significantly more likely to exhibit antigen-specific production of TNFα without IL-10 (P = 0.003). While TNFα-producing CD4(+) T cells were not independently associated with future protection, the absence of cells producing this inflammatory cytokine was associated with the phenotype of asymptomatic infection. Together these data indicate that the functional phenotype of the malaria-specific T cell response is heavily influenced by malaria exposure intensity, with IFNγ/IL10 co-producing CD4(+) T cells dominating this response among highly exposed children. These CD4(+) T cells may play important modulatory roles in the development of antimalarial immunity.
authors.affiliation: Department of Medicine, San Francisco General Hospital, 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, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Ijeoma
authors.initials: I
authors.lastname: Eccles-James
authors.affiliation: Department of Medicine, San Francisco General Hospital, 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: Samuel
authors.initials: S
authors.lastname: Wamala
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Charles
authors.initials: C
authors.lastname: Ebusu
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Muhindo
authors.affiliation: Infectious Diseases Research Collaboration, Kampala, Uganda.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Arinaitwe
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Briggs
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Bryan
authors.initials: B
authors.lastname: Greenhouse
authors.affiliation: Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Tappero
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, San Francisco General Hospital, 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, San Francisco General Hospital, 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: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology*; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology*; D008288:Malaria / Q000097:blood / Q000453:epidemiology / Q000276:immunology* / Q000473:pathology; D008297:Male; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology; D014454:Uganda / Q000453:epidemiology
chemical_list: C573415:IFNG protein, human; C508609:IL10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma