NK cell cytotoxicity is transiently enhanced during acute malaria and modulated by the host microenvironment
Pengjun Xi, Patrick A. Sandoz, Maximilian Julius Lautenbach, Eleni Bilev, Björn Önfelt, Anna Färnert, Quirin Hammer, Christopher Sundling
Pengjun Xi, Patrick A. Sandoz, Maximilian Julius Lautenbach, Eleni Bilev, Björn Önfelt, Anna Färnert, Quirin Hammer, Christopher Sundling
View: Text | PDF
Research Article Immunology Infectious disease Inflammation

NK cell cytotoxicity is transiently enhanced during acute malaria and modulated by the host microenvironment

Abstract

Natural killer (NK) cells are pivotal in the early immune response to Plasmodium falciparum infection, yet their functional dynamics and regulation remain incompletely understood. In a longitudinal study of patients with malaria in a nonendemic setting, we observed a transient but potent activation of NK cell cytotoxicity during acute malaria, characterized by rapid granzyme B–mediated killing and elevated expression of genes associated with cytotoxicity (PRF1, GZMB, and GZMA). This heightened activity was supported by increased plasma levels of granzymes and proinflammatory cytokines, which enhanced NK cell function in vitro. However, plasma samples from clinical malaria also contained inhibitory mediators, including soluble cytokine receptors, which dampened NK cell responses. These findings reveal that the host microenvironment orchestrates a tightly regulated NK cell response that potentiates cytotoxicity during acute infection and rapidly downmodulates it after treatment. Understanding this balance between activation and suppression may inform strategies to harness NK cells for malaria control while minimizing immunopathology.

Authors

Pengjun Xi, Patrick A. Sandoz, Maximilian Julius Lautenbach, Eleni Bilev, Björn Önfelt, Anna Färnert, Quirin Hammer, Christopher Sundling

×

Figure 2

NK cells have increased killing capacity during acute malaria infection.

Options: View larger image (or click on image) Download as PowerPoint
NK cells have increased killing capacity during acute malaria infection....
(A) Schematic overview of NK cell killing mechanisms and contact types assessed using A498GBDR dual-reporter target cells. (B) Total killing by CD56+ NK cells from acute, day 10, and convalescent (12-month) time points. Each line represents a patient with malaria. (C) Killing efficiency normalized to the number of NK cells per microwell. (D) Killing capacity of CD56+ NK cells under different stimulation conditions (IL-2, IL-15, and/or CetAb antibody). (E) Killing efficiency of sorted NK cell subsets from acute and convalescent time points, stimulated with IL-2, IL-15, and CetAb antibody. NA indicates that the marker was not assessed during cell sorting. (F) Time-resolved killing efficiency of CD56+ NK cells over the first 24 hours of coculture. Each dot represents a microwell (n = 35–37 microwells) in D–F. (G) Ratio of killing efficiency, shown in F, between acute and convalescent NK cells over time. Each dot represents the ratio at a given time point. (H) Distribution of killing mechanisms used by CD56+ NK cells. (I) Time from NK cell–target cell contacts to target cell lysis for granzyme B– and caspase-8–mediated killing (n = 93–595 killing events). (J) Killing time for events classified as “other,” including atypically fast or slow killing events (n = 119 and 158 killing events). (K) Contact types used during granzyme B–mediated killing by CD56+ NK One-way ANOVA followed by 2-tailed paired (B and C) or 2-tailed unpaired (D–F and I) t tests with correction for multiple comparisons; unpaired t test for J. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (H–K) One representative donor based on 36 microwells, see Supplemental Figure 4 for the second donor.