Keystone Malaria Symposium
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P Jagannathan, F Nankya, I Eccles-James, A Auma, K Bowen, S Wamala, C Ebusu, M Kakuru, J Briggs, J Tappero, F Kaharuza, M Kamya, G Dorsey, M Feeney. Malaria-specific T cell responses in young Ugandan children living in a high transmission setting. Abstract accepted to Keystone Malaria Symposium Jan 2013.
Background: Although there is evidence that T cells are critical for protection from malaria, reliable in vitro correlates of T cell immunity in naturally exposed children are lacking. A better understanding of such correlates will assist in developing vaccines and other control interventions.
Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 221 HIV-uninfected 4-year old children with known prior malaria history (incidence per person year (ppy)) and days since last malaria episode) from a cohort study in Tororo, Uganda. Responses to 7 pre-erythrocytic and 3 erythrocytic-stage antigens were assessed by ex vivo IFNg elispot. Remaining PBMC were stimulated with uninfected RBCs, Plasmodium falciparum-infected red blood cells (iRBC), schizont extract (SE), or controls in a subset of children and assessed by intracellular cytokine staining (ICS) or for proliferation by carboxyfluorescein succinimidyl ester (CFSE). Statistical analyses were performed using chi square and linear regression.
Results: The prior incidence of malaria in this cohort ranged from 0-12 ppy. Responses to pre-erythrocytic and erythrocytic antigens were detectable in 32% and 47% of children respectively. Responses to merozoite surface protein-1 were most common (43%), and significantly so in children with malaria <30 days previously versus >90 days previously (63% vs. 7%, p=0.002). The frequency of iRBC-stimulated CD4+ T cells producing IFNγ and IL10 correlated with prior malaria incidence (r2=0.29, p=0.005), while that of iRBC-stimulated γδ+ T cells producing IFNγ and TNFα was inversely correlated with prior incidence (r2=0.44, p =0.006). A greater proportion of Vδ2+ γδ+ T cells divided after stimulation with SE in children with <2 episodes of malaria in the prior year in comparison to children with >6 episodes of malaria in the prior year (median 56.9% vs 13.7% cells divided, p=0.0012).
Conclusions: In naturally exposed children, iRBC-stimulated, malaria-specific IFNγ/IL10producing CD4+ T cells and a lack of malaria-specific γδ+ T cells represent novel correlates of exposure to malaria and may play important immunomodulatory roles in the development of immunity to malaria.