ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Repeated Plasmodium falciparum infection in humans drives the clonal expansion of an adaptive γδ T cell repertoire (#252)

Anouk von Borstel 1 , Priyanka Chevour 1 , Daniel Arovski 1 , Jelte M.M. Krol 2 3 , Lauren J. Howson 1 , Andrea A. Berry 4 , Cheryl L. Day 5 , Paul Ogongo 6 7 , Joel D. Ernst 6 , Effie Y.H. Nomicos 8 , Justin A. Boddey 2 3 , Edward M. Giles 9 10 , Jamie Rossjohn 1 11 12 , Boubacar Traore 13 , Kirsten E. Lyke 4 , Kim C. Williamson 14 , Peter D. Crompton 15 , Martin S. Davey 1
  1. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  3. University of Melbourne, Melbourne, VIC, Australia
  4. Vaccine Development and Global Health, University of Maryland, School of Medicine, Baltimore, MD, USA
  5. Department of Microbiology and Immunology, Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA
  6. Division of Experimental Medicine, Department of Medicine, UCSF School of Medicine, San Fransisco, CA, USA
  7. Department of Tropical and Infectious Diseases, Institute of Primate Research, National Museums of Kenya, Nairobi, Kenya
  8. Parasitology and International Programs Branch, Division for Microbiology and Infectious Diseases, NIAID, NIH, Bethesda, MD, USA
  9. Department of Paediatrics, Monash University, Clayton, VIC, Australia
  10. Centre for Innate Immunity and Infectious Disease, Hudson Institute of Medicine, Clayton, VIC, Australia
  11. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia
  12. Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, United Kingdom
  13. Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali
  14. Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
  15. Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD, USA

Repeated Plasmodium falciparum infections drive the development of clinical immunity to human malaria. However, immunological mechanisms underpinning this response are only partially understood. γδ T cells have been linked to clinical protection from malaria, but how adaptive-like Vδ1+ T cells respond to repeated P. falciparum infections is unclear. We investigated the impact of repeated P. falciparum infections on γδ T cell subsets and the γδ T cell receptor (TCR) repertoire in humans. We studied peripheral blood samples from Australian children, Malian children naturally exposed to malaria, and U.S. adults serially challenged with four repeated controlled human malaria infections (CHMIs). Clonally expanded cytotoxic Vδ1effector T cells were a major component of the γδ T cell compartment in Malian children compared to malaria-naïve Australian children. Sequential CHMIs initiated a robust innate-like Vδ2+ T cell response to three P. falciparum infections in malaria-naïve U.S. adults, however, these cell frequencies declined between infections and were not sustained after the fourth infection. In contrast, Vδ1+ T cell frequencies increased after repeated infection and correlated with clinical immunity to malaria. Populations of Vδ1naive T cells differentiated into cytotoxic Vδ1effector cells concomitant with waves of clonal selection after each infection. Finally, Vδ1+ T cells from individuals with a history of malaria were licensed for in vitro P. falciparum parasite reactivity. Together, our study indicates that repeated P. falciparum infections drive the clonal expansion of an adaptive γδ T cell repertoire and establishes a role for Vδ1+ T cells in the human immune response to malaria.