A novel population of memory‐activated natural killer cells associated with low parasitaemia in Plasmodium falciparum‐exposed sickle‐cell trait children

Abstract

Objectives. The sickle-cell trait phenotype is associated with protection from malaria. Multiple molecular mechanisms have been proposed to explain this protection, but the role of the host immune system has been poorly investigated. We hypothesised that cellular immunity to malaria may develop differently in sicklecell trait children (HbAS) and children with normal haemoglobin (HbAA) repeatedly exposed to Plasmodium falciparum (Pf). Methods. Paired samples collected prior to the Pf transmission season and during the first malaria episode of the ensuing transmission season from HbAS and HbAA children were analysed by multiplex bead-based assay and comprehensive multidimensional flow cytometry profiling. Results. Cellular immune profiles were enriched in HbAS relative to HbAA children before the start of the Pf transmission season, with a distinct NK subset. These cells were identified as a novel subset of memory-activated NK cells characterised by reduced expression of the ecto-enzyme CD38 as well as co-expression of high levels of HLA-DR and CD45RO. The frequency of this NK subset before the transmission season was negatively correlated with parasite density quantified during the first malaria episode of the ensuing transmission season. Functional assessment revealed that these CD38 dim CD45RO + HLA-DR + NK cells represent a important source of IFN-c. Conclusion. Our data suggest that this novel memory-activated NK cell subset may contribute to an accelerated and enhanced IFN-cmediated immune response and to control of parasite density in individuals with the sickle-cell trait. This distinct cellular immune profile may contribute to predispose HbAS children to a relative protection from malaria.

Regulation of the human NK cell compartment by pathogens and vaccines

“…In support of this hypothesis, in COVID‐19 patients these adaptive cells also express Ksp37, a marker of cytotoxic lymphocytes associated with lung disease, 77 and, despite their lower intrinsic proliferative capacity, also express markers of recent proliferation 74 . This is reminiscent of the increased proliferative capacity of adaptive CD45RO + NK cells in chronic malaria infection as discussed above 61,74 and is also consistent with reports of enrichment of highly differentiated CD56 dim CD57 + NK cells with high proliferative capacity in the peripheral blood in a patient with SARS‐CoV‐2 infection and acute respiratory distress syndrome (ARDS) 78 …”

“…The potential for chronic or repeated malaria infections to influence NK cell phenotype and function is illustrated by the identification of a novel, activated CD38 + HLA − DR + CD45RO + NK cell population in individuals with sickle cell trait who have persistent low‐density parasitaemia 61 . A possible explanation for this is that chronic in vitro stimulation of NK cells via NKG2C in combination with IL‐15 induces CD45 isoform switching on CD57 + NKG2C + cells, resulting in a CD45RO + population with high proliferative potential, characteristic of central memory T cells 14 .…”

“…The potential for chronic or repeated malaria infections to influence NK cell phenotype and function is illustrated by the identification of a novel, activated CD38 + HLA À DR + CD45RO + NK cell population in individuals with sickle cell trait who have persistent low-density parasitaemia. 61 A possible explanation for this is that chronic in vitro stimulation of NK cells via NKG2C in combination with IL-15 induces CD45 isoform switching on CD57 + NKG2C + cells, resulting in a CD45RO + population with high proliferative potential, characteristic of central memory T cells. 14 Increased expression of checkpoint inhibitors including TIM3 and PD-1 has also been observed after repeated malaria exposure with increasing age in endemic populations, 62 again with parallels to the emergence of LAG3 and PD1 + adaptive NK cells after activating receptor (NKp30, NKG2D, NKG2C) or HCMV-mediated activation in vitro.…”

HLA-DR-expressing NK cells: Effective killers suspected for antigen presentation

“…First of all, HLA-DR expression seems to be associated with IFN production, 13,16,29,33,34 and a couple of studies have demonstrated a direct correlation between these two values. 21,36,50 It should be noted, however, that a causal relationship can be built in both directions: HLA-DR + ("activated") NK cells may produce more IFN , 13 and IFN produced by NK cells can induce HLA-DR expression as a result of auto stimulation, as discussed by Yano et al 21 These two processes may go in parallel, maintaining a loop of positive feedback.…”

“…Based on the existing data describing HLA‐DR‐expressing NK cells both in vivo and in vitro, the following functional features of this subset can be distinguished. First of all, HLA‐DR expression seems to be associated with IFNγ production, 13,16,29,33,34 and a couple of studies have demonstrated a direct correlation between these two values 21,36,50 . It should be noted, however, that a causal relationship can be built in both directions: HLA‐DR + (“activated”) NK cells may produce more IFNγ, 13 and IFNγ produced by NK cells can induce HLA‐DR expression as a result of auto stimulation, as discussed by Yano et al 21 .…”