Th154 - Diminished Vδ2+ γδ T cell Cytokine Production and Degranulation Following in vitro Malaria Exposure

Natural immunity to Plasmodium falciparum (Pf) malaria provides some protection against symptomatic disease in older children and adults, but is unable to eliminate parasite replication. A major component of this incomplete immunity is attenuation of cytotoxic, pro-inflammatory responses by innate cells like Vδ2+ γδ T cells following repeated malaria exposure. We are utilizing several innovative approaches to identify mechanisms underlying Vδ2+ T cell dysfunction, including replicating this phenotype in vitro and leveraging samples from a longitudinal cohort in Uganda. Purified malaria-naïve Vδ2+ cells stimulated in vitro with Pf-infected red blood cells (iRBCs) or the phosphoantigen HMBPP produce less TNFα and IFNγ and degranulate less in response to secondary stimulation compared to unstimulated cells. In contrast, stimulation with iRBCs or HMBPP does not impact the ability of the cells to respond to control stimuli, indicating that the reduced response is Pf-specific. Addition of monocytes to Vδ2+ T cells –particularly at higher ratios—reduced responses compared to unstimulated cells or cells stimulated without monocytes. Together, these results support both cell-intrinsic and extrinsic mechanisms contributing to reduced Vδ2+ T cell responsivity following malaria exposure. In parallel, we are performing paired RNA-Seq and ATAC-Seq experiments among Vδ2+ cells from Ugandan children at multiple timepoints in order to define transcriptional and epigenetic changes underlying altered cell function following repeated malaria. Ultimately, this work could deepen our understanding of mechanisms driving inefficient acquisition of antimalarial immunity and could inspire novel therapeutic approaches that enhance parasite clearance and/or reduce disease severity.