Baseline Treg frequency, Treg-associated immune checkpoint responses, and plasma IL-10 responses during controlled human malaria infection in semi-immune Kenyan adults: a secondary analysis of the CHMI-SIKA Study.

BackgroundExperimental infection with Plasmodium falciparum in malaria-naive European adults induces CD25+FoxP3+ regulatory CD4+ T cell (Treg) expansion. Increased Treg activity is associated with reduced inflammatory cytokine responses and increased parasite growth. Whether similar associations occur in semi-immune adults from malaria-endemic regions remains unclear. In this study, we aimed to examine how inflammatory cytokines, regulatory cytokines, and Tregs influence parasitic and clinical outcomes during controlled human malaria infection in semi-immune adults from three regions in Kenya with differing degrees of P falciparum exposure.MethodsThis secondary analysis of the CHMI-SIKA study characterised phenotypes and frequencies of circulating Tregs and cytokine concentrations during experimental malaria infection in 105 Kenyan adult participants from three regions of Kenya with varying degrees of previous exposure: Ahero (moderate to high), Kilifi South (moderate), and Kilifi North (low). Upon inoculation with P falciparum sporozoites, participants were followed up for 35 days. During this period, parasite growth and clinical symptoms were monitored, and immunological samples were collected. Participants were categorised as either requiring antimalarial treatment (treated) or not requiring it (untreated), based on a predefined protocol threshold. This classification reflected their relative immunological ability to control parasite growth and expression of malaria symptoms. In a randomly selected subset of 28 participants, we assessed the expression profiles of 91 genes with established roles in Treg function in fluorescence-activated cell sorting-isolated Tregs using a multiplex quantitative PCR assay.FindingsTreated participants had higher baseline Treg frequencies than those untreated. At day 8, sorted Tregs showed 15 differentially expressed genes between treated and untreated participants, including immune checkpoint markers TNFRSF18, LRRC32, and KLRG1. Interleukin (IL)-10 concentrations were higher, and transforming growth factor-β concentrations were lower in the treated participants than in the untreated participants.InterpretationHigh basal Treg frequencies before experimental challenge with P falciparum malaria are associated with Treg-specific upregulation of TNFRSF18 (GITR/CD357), LRRC32 (GARP), and KLRG1; increased P falciparum parasite growth; and high IL-10 concentrations in semi-immune adults. Innovative host-directed therapies that counteract regulatory T cell activity may enhance vaccine immunogenicity in malaria-endemic regions, thereby improving the effectiveness of malaria control measures. In turn, effective malaria control may confer broader immunological benefits for individuals living in these settings.FundingUK Medical Research Council/Foreign Commonwealth and Development Office (MRC/FCDO), part of the EDCTP2 programme supported by the EU, and Wellcome.