Functional diversification of T cells and their role in the response to childhood malaria 2035

Abstract Description Gamma delta (γδ) T cells are unconventional T cells that resemble both innate- and adaptive-like lymphocytes. Human Vγ9Vδ2 T cells possess intrinsic, MHC-independent responsiveness to Plasmodium phosphoantigens (pAg) released in the blood stage of malaria infection. Engagement of the γδ T cell receptor (TCR) by pAg-bound butyrophilins results in Vγ9Vδ2 T cell expansion, pro-inflammatory cytokine production, and release of cytotoxic granules that mediate parasite killing. Repeated malaria infection, however, leads to a reduction in circulating Vγ9Vδ2 T cells and upregulation of immunomodulatory molecules, including NK receptors, that correlates with less severe symptomatology upon infection. We explore phenotypic and functional differences of γδ T cells in Ugandan children with high versus low malaria exposure, employing two single-cell Methods scRNA-seq of sorted γδ T cells and high-parameter spectral flow cytometry analysis of PBMCs. With scRNA-seq we identify γδ T cell clusters with distinct gene expression between exposure groups. Using spectral flow, we observe significantly different expression of inhibitory NK receptors – KIRs 2DL1, 2DL2/3, and 3DL1, LILRB1, and NKG2a – on γδ T cell subsets. We find that expression of these NK receptors associates uniquely with TCR- versus Fc-mediated Vγ9Vδ2 T cell responses, suggesting functional regulation. Integrating this data, we further our understanding of γδ T cell biology to better understand their protective role in malaria. Funding Sources This work was supported in part by grants from the National Institute of Allergy and Infectious Diseases (NIAID) grants NIH/NIAID R01-AI093615 and NIH/NIAID K24-AI113002. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)