Date Published: January 9, 2014
Publisher: Public Library of Science
Author(s): Prasanna Jagannathan, Ijeoma Eccles-James, Katherine Bowen, Felistas Nankya, Ann Auma, Samuel Wamala, Charles Ebusu, Mary K. Muhindo, Emmanuel Arinaitwe, Jessica Briggs, Bryan Greenhouse, Jordan W. Tappero, Moses R. Kamya, Grant Dorsey, Margaret E. Feeney, Jean Langhorne.
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.
Clinical immunity to malaria eventually develops in endemic populations, but only after repeated infections with significant morbidity to both individuals and their communities . Studies in regions of high malaria transmission intensity have consistently shown that the incidence of severe disease decreases considerably after the first years of life, but sterile immunity (i.e. protection against parasitemia) develops rarely if ever , . Moreover, previously immune individuals may lose protection against symptomatic infection in the absence of continuous exposure , . The reasons underlying the slow acquisition of clinical immunity and the failure to develop sterilizing immunity are unclear, but may include parasite diversity and evasion , age-related differences in immune responses –, and/or host immunoregulatory mechanisms induced by the parasite –. As the incidence of malaria continues to be high in many parts of Africa despite insecticide-treated bednets and artemisinin-based combination therapy –, there is a tremendous need to better understand mechanisms of immunity to malaria in naturally exposed populations. The identification of immunologic correlates of exposure and protection in naturally exposed children would significantly help with the rational design of vaccines and other malaria control interventions.
In this cohort of young children living in an area of very high transmission intensity in Uganda, very little evidence of clinical immunity had emerged by five years of age. In this setting, the functional phenotype of the malaria-specific CD4+ T cell response was significantly influenced by prior malaria exposure; with less prior malaria, the overall malaria-specific CD4+ T cell response was more inflammatory (TNFα-producing), but with heavier exposure, the overall malaria-specific response was more regulatory (IL-10 producing). To our knowledge, this is the first study to show that Th1 IFNγ/IL-10 co-producing cells constitute the dominant population of CD4+ T cells responding to malaria in heavily exposed children. Moreover, we found no evidence that these IFNγ/IL-10 co-producing cells were associated with protection from future malaria.