Vδ2 T cell activation by malaria is enhanced in second infection via the cell extrinsic cytokine milieu

{gamma}{delta} T cells play critical roles in innate immunity to Plasmodium falciparum malaria, yet their functional heterogeneity and memory-like dynamics during first and subsequent infections remain poorly defined. Using longitudinal single-cell RNA sequencing, ex vivo phenotyping and in vitro functional analysis of {gamma}{delta} T cells in controlled human malaria infection (CHMI), we dissect their activation mechanisms and functions. During first infection, V{delta}2 T cells dominated the responses, expanding into inflammatory and cytotoxic cells. Despite upregulation of antigen-presenting-like markers and CD16, V{delta}2 T cell activation remained TCR-dependent, and these cells had no capacity to phagocytose parasites nor present antigen to CD4+ T cells. Leveraging a Phase I clinical study of type I IFN signalling blockade with JAK2 inhibitor ruxolitinib in CHMI, including rechallenge, we show that V{delta}2 T cell activation is dependent on JAK/STAT signalling. In second malaria infection V{delta}2 T cell responses are memory-like, with higher and more rapid activation, and robust induction of cytotoxic and activated terminal effector memory phenotypes. These memory-like cell responses were linked to cell-extrinsic factors, with increased systemic inflammation during second infection associated with enhanced V{delta}2 T cell activation. Mechanistically we demonstrate that cytokines IL-12, IL-15 and IL-18, synergize with TCR-dependent activation by malaria parasites to enhance V{delta}2 T cell responses. Memory-like V{delta}2 T cells in second infection were not associated with parasite control but instead linked to inflammation and markers of disease severity. Together, these data identify key mechanisms of V{delta}2 T cells activation and highlight that therapeutically targeting these cells may benefit immunopathology without compromising parasite control during malaria.