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Abstract
Background Allogeneic hematopoietic stem cell transplantation (HSCT) has been developed as a major treatment option for leukemia and lymphoma patients. HSCT transfers pluripotent stem cells to reconstitute patients’ hematopoiesis with functional immune cells. Although the clinical practice of HSCT has been extensively studied and significantly improved over the last decades, the leading cause of late morbidity and mortality in patients remains chronic graft-versus-host disease (cGVHD). In published studies of cGVHD, natural killer (NK) cells have been recognized as one of the earliest immune cells reconstituted in post-HSCT patients. NK cells are known to suppress cGVHD with the potential, not limited to cytotoxicity, to restrain pathogenic cell types. Respectively, subsets of CD56bright NK cells, previously categorized as immature, are suggested to play a regulatory function in cGVHD patients. However, the knowledge gap pertains to the molecular mechanisms by which subsets of NK cells mediate the suppression of cGVHD in response to distinct environmental cues.
Methods We performed single-cell RNA sequencing on NK cells isolated from the PBMC of patients who developed cGVHD (5 patients) or not (6 patients). With knowledge from previously published data, we performed in vitro assays on human NK cells collected from healthy donors to confirm the new findings from single-cell RNA sequencing.
Results In our single-cell RNA sequencing results, we were able to identify distinct subsets of NK cells (figure 1A), which have significantly different percentages between the two groups of patients (figure 1B). Besides quantitative differences, transcriptomic differences were also observed among NK cells. More importantly, transcriptionally, we found NK cell subsets responded differently to IFN-α and IL-12/IL-18 between the two groups of patients (figure 1C). Respectively, NK cells from chronic GVHD patients have a considerate reduction of gene expression in response to IL-12/IL-18, with responses shifted toward IFN-α stimulation. In the previous publication, α-Ketoglutaric acid (aKG), one of the key intermediates in the TCA cycle, has been identified to be significantly increased in the plasma of chronic GVHD patients compared. By in vitro treatment of human NK cells with aKG, we confirmed that aKG alone can alter NK cell differentiation and responses to cytokines including IL-12/IL-18 and IFN-α via epigenetic modification.
Conclusions Our study has revealed a novel mechanism of how the differentiation and function of human NK cells can be epigenetically reprogrammed by aKG, leading to different cGVHD progression. This finding has high translational relevance and can contribute to the treatment of cGVHD patients.
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