- May 1, 2026
Topic/Product:
Inflammation Panel 250, malaria
Disease Area:
Infectious Disease, Inflammation
Sample Type:
Cell Culture Supernatant
Abstract
γδ 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 γδ T cells in controlled human malaria infection (CHMI), we dissect their activation mechanisms and functions. During first infection, Vδ2 T cells dominated the responses, expanding into inflammatory and cytotoxic cells. Despite upregulation of antigen-presenting-like markers and CD16, Vδ2 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 Vδ2 T cell activation is dependent on JAK/STAT signalling. In second malaria infection Vδ2 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 Vδ2 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 Vδ2 T cell responses. Memory-like Vδ2 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 Vδ2 T cells activation and highlight that therapeutically targeting these cells may benefit immunopathology without compromising parasite control during malaria.
Authors and Affiliations
Nicholas L. Dooley1,2,3, Zuleima Pava1, Dean Andrew2, Natalie E. Stevens4,5, Teija Frame2,
Jessica R. Loughland1, Megan S.F. Soon2, Damian A. Oyong1, Fabian de Labastida Rivera2,
Reena Mukhiya1, Julianne Hamelink1, Luzia Bukali2, Jessica Engel2, Feargal J. Ryan4, David J.
Lynn4,5, Moses R. Kamya6,7, Isaac Ssewanyana6, Rebecca Webster2, James S. McCarthy6,
Bridget E. Barber2, J. Alejandro Lopez2,3, Chris Engwerda2,3 & Michelle J. Boyle1,2
1 Life Sciences Department, Burnet Institute, Melbourne, Australia
2 Infection and Inflammation Department, QIMR Berghofer Medical Research Institute,
Brisbane, QLD, Australia
3 School of Environment and Science, Griffith University, Brisbane, QLD, Australia
4 College of Medicine and Public Health, Flinders Health and Medical Research Institute,
Flinders University, Bedford Park, SA, Australia.
5 Systems Immunology Laboratory, Precision Medicine Theme, South Australian Health and
Medical Research Institute, Adelaide, SA, Australia.
6 Infectious Diseases Research Collaboration, Kampala Uganda
7 Makerere University, Kampala, Uganda.