Clinical & Translational Immunology (Jan 2024)

Natural killer cell antibody‐dependent cellular cytotoxicity to Plasmodium falciparum is impacted by cellular phenotypes, erythrocyte polymorphisms, parasite diversity and intensity of transmission

  • Stephen Tukwasibwe,
  • Savannah Nicole Lewis,
  • Yoweri Taremwa,
  • Kattria van derPloeg,
  • Kathleen D Press,
  • Maureen Ty,
  • Felistas Namirimu Nankya,
  • Kenneth Musinguzi,
  • Evelyn Nansubuga,
  • Florian Bach,
  • Martin Chamai,
  • Martin Okitwi,
  • Gerald Tumusiime,
  • Annettee Nakimuli,
  • Francesco Colucci,
  • Moses R Kamya,
  • Joaniter I Nankabirwa,
  • Emmanuel Arinaitwe,
  • Bryan Greenhouse,
  • Grant Dorsey,
  • Philip J Rosenthal,
  • Isaac Ssewanyana,
  • Prasanna Jagannathan

DOI
https://doi.org/10.1002/cti2.70005
Journal volume & issue
Vol. 13, no. 11
pp. n/a – n/a

Abstract

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Abstract Objectives Natural killer (NK) cells make important contributions to anti‐malarial immunity through antibody‐dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear. Methods We compared the functions and phenotypes of NK cells from malaria‐exposed and malaria‐naive donors, and then varied the erythrocyte genetic background, Plasmodium falciparum strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation. Results Natural killer cells from malaria‐exposed adult Ugandan donors had enhanced ADCC, but an impaired pro‐inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria‐naive adult North American donors. Cellular phenotypes from malaria‐exposed donors reflected this specialisation for ADCC, with a compartment‐wide downregulation of the Fc receptor γ‐chain and enrichment of highly differentiated CD56dim and CD56neg populations. NK cell degranulation was enhanced in response to opsonised P. falciparum schizonts cultured in sickle cell heterozygous erythrocytes relative to wild‐type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont‐specific IgG levels. However, degranulation was lowered in response to opsonised field isolate P. falciparum schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays. Conclusion This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.

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