Article

IFNγ/IL-10 Co-producing Cells Dominate the CD4 Response to Malaria in Highly Exposed Children

National Institute for Medical Research, United Kingdom
PLoS Pathogens (Impact Factor: 7.56). 01/2014; 10(1):e1003864. DOI: 10.1371/journal.ppat.1003864
Source: PubMed

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.

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    • "Despite its importance in controlling immune responses in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohns's disease, and type 1 diabetes, administration of IL-10 has never been very effective and in some cases is detrimental, even though animal model studies show that the removal of IL-10 can exacerbate disease caused by infectious agents (Kugelberg, 2014; Saxena et al., 2015). IL-10, particularly from CD4 T cells, is important for down-regulating host responses and pathology in experimental malaria (Freitas do Rosário et al., 2012; Villegas-Mendez et al., 2013), and its expression in these cells is increased in humans with, or after, acute malaria (Jagannathan et al., 2014). However, IL-10 is produced by many different cells during rodent malaria infection (Freitas do Rosário et al., 2012; Liu et al., 2013), is regulated differently in the various cells (Gabryšová et al., 2014), and is involved in multiple pathways to suppress, or even stimulate, immune responses. "
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