Ex vivo cytokine responses and metabolic reprogramming are associated with γδ T cell differentiation in Plasmodium falciparum placental malaria

Background: associations between cytokines, metabolic profiles and γδ T-cell differentiation in women with PM. Methods: plasma levels of IL-8, IL-33, and IL-35 were quantified by Luminex assay or ELISA. Immunometabolic profiles were assessed in a subset of 15 samples from uninfected women following cell stimulation with phytohemagglutinin (PHA) by SCENITH assay. Results: analyses showed that γδ T cell-modulating cytokine IL-8 were associated, in a compartment-dependent manner, with down-regulation of immunoregulatory markers TIM-3 and PD-1. Interestingly, IL-8 and IL-33 were associated with increased frequency of the TEMRA cell phenotype in peripheral blood, consistent with enhanced differentiation of naïve γδT cells during PM. Metabolic profiling of the different cell types further established an enhanced mitochondrial metabolic activity in predominantly terminally differentiated γδ T cells in PBMC, compared to the mainly glycolytic activities of non-terminally differentiated cells in CBMC and IVBMC. Conclusion: Placental malaria is associated with a compartment-specific memory γδ T cell differentiation, with cytokines and metabolic reprogramming regulating exhaustion. These findings reveal key regulatory processes that determine the function of γδ T cells during placental malaria, which constitute potential targets for new therapeutic intervention against PM.