1011 Metabolic reprogramming alters natural killer cell responses in chronic graft-versus-host disease
Notice bibliographique
Résumé
<h3>Background</h3> 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 CD56<sup>bright</sup> 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. <h3>Methods</h3> 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 <i>in vitro</i> assays on human NK cells collected from healthy donors to confirm the new findings from single-cell RNA sequencing. <h3>Results</h3> 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 <i>in vitro</i> 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. <h3>Conclusions</h3> 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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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».