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Improved hematopoietic stem cell transplantation upon inhibition of natural killer cell-derived interferon-gamma.

ABSTRACT: Hematopoietic stem cell transplantation (HSCT) is a frequent therapeutic approach to restore hematopoiesis in patients with hematologic diseases. Patients receive a hematopoietic stem cell (HSC)-enriched donor cell infusion also containing immune cells, which may have a beneficial effect by eliminating residual neoplastic cells. However, the effect that donor innate immune cells may have on the donor HSCs has not been deeply explored. Here, we evaluate the influence of donor natural killer (NK) cells on HSC fate, concluded that NK cells negatively affect HSC frequency and function, and identified interferon-gamma (IFNγ) as a potential mediator. Interestingly, improved HSC fitness was achieved by NK cell depletion from murine and human donor infusions or by blocking IFNγ activity. Thus, our data suggest that suppression of inflammatory signals generated by donor innate immune cells can enhance engraftment and hematopoietic reconstitution during HSCT, which is particularly critical when limited HSC numbers are available and the risk of engraftment failure is high.

SUBMITTER: Lobo de Figueiredo-Pontes L

PROVIDER: S-EPMC8365098 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-?) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator ?-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-? production. ?-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and ?-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, ?-galactosylceramide (?-GalCer) using a mouse model. Pharmacologic targeting of ?-catenin activity with ICG001, as well as myeloid-specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-? responses. By contrast, within several hours of ?-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired ?-GalCer-induced IFN-? responses, independent of ?-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/?-catenin signaling that curbs IFN-? responses, but that, subsequently, Wnt ligands sustain IFN-? expression independent of ?-catenin activity. Our analyses in ICG001-treated mice confirmed a role for ?-catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL-4 response, suggesting that IL-4 production by NKT cells in response to ?-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and ?-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of ?-catenin to NKT cell functions.

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Improved hematopoietic stem cell transplantation upon inhibition of natural killer cell-derived interferon-gamma.

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