Malaria-induced innate immune modulation of an atypical cellular population plays a substantial role in driving and maintaining immunity against malaria, a new study from scientists at Stanford University has demonstrated. The findings were published in the article, “Malaria-driven expansion of adaptive-like functional CD56-negative NK cells correlates with clinical immunity to malaria,” which was published in the journal Science Translational Medicine.

“This work identifies a clear role for CD56 negative cells in innate/adaptive immune bridging and has important implications for host immune responses to vaccines and other infections in malaria-endemic settings,” said Prasanna Jagannathan, PhD, an assistant professor of infectious diseases and geographic medicine at Stanford University and the senior author of the study.

“Since ongoing malaria exposure seems to be required to maintain these cells, loss of this cell subset may also play a role in the resurgence and/or delay of malaria after withdrawal of effective malaria control interventions,” Jagannathan added.

Earlier studies have suggested that immunity to malaria, particularly direct parasite recognition and antibody-dependent cellular toxicity, depends on a form of immune cells called natural killer (NK) cells, but the effect of repeated exposure to malaria on NK cell responses has remained ambiguous.

“In this study, we characterized the NK cell response among 264 children followed in the East African International Centers of Excellence in Malaria Research (ICEMR) cohorts in Eastern Uganda,” the authors noted.

The researchers followed the children over time across a range of malaria transmission intensities. To characterize NK cell responses, they used multiparameter flow cytometry, CITE-seq to index cellular transcriptomes and epitopes, EpiTOF for epigenetic profiling, ATAC-seq to assay for transposase-accessible chromatin, and functional assays.

NK cells are conventionally classified based on the expression of CD56 and CD16, with  CD56dimCD16+ NK cells forming the majority of NK cells in peripheral blood. The recent application of single-cell approaches has begun to uncover the rich cellular diversity and complexity of NK cell subtypes.

For instance, recent studies have identified a subset of CD56dimCD16+ NK cells that express low levels of the transcription factor PLZF (promyelocytic leukemia zinc finger) and the signaling factor FcRγ. The cellular sub-class exhibits heightened antibody dependent cellular cytotoxicity (ADCC) against the malarial parasite, Plasmodium falciparum, and is associated with resistance to malaria in children in Mali.

“Whether CD56neg NK cells expand after repeated malaria, have functional capabilities, and/or play a role in clinical immunity to malaria is unknown,” the authors noted.

Typically, human NK cells circulating through the bloodstream are identified through CD56 expression. However, in this study, the researchers demonstrated that repeated exposure to malaria is associated with the expansion of a highly functional atypical subset of NK cells that do not express the cell-surface glycoprotein CD56 (CD56neg cells), and strongly correlate to acquiring immunity against malaria. They also showed that in the absence of continuous exposure to malaria, the frequencies and function of this subset of NK cells rapidly decline.

“Our data suggest that CD56 negative NK cells make up a significant fraction—and in many cases the majority—of circulating NK cells among children living in a high malaria transmission setting,” the authors noted.

CD56neg cells, the researchers showed differences transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including those that express low levels of PLZF and FcRγ. The CD56neg NK cells also displayed greater ADCC than CD56dim cells. The investigators also showed higher levels of CD56neg cells were linked to protection against symptomatic malaria and high parasite densities.

When malaria transmission was markedly reduced, the frequencies of these CD56neg NK cells declined quickly, indicating continuous exposure to the malarial parasite is necessary to maintain high levels of this atypical subclass of NK cells.

“Understanding whether the loss of this cellular immune response plays a role in the resurgence and/or delay of malaria after withdrawal of effective malaria control interventions remains to be determined,” the authors noted.

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