Biology subjects

Uhrberg, M.

Publications and source records attributed to Uhrberg, M..

5 recordsLinked to original sources

bioRxiv2026

CMV Replication Drives IFNγ-Mediated Sensitization of AML Cells to Cytotoxic Killing Through the NKG2C-HLA-E Axis

Human cytomegalovirus (CMV) infection represents a significant risk factor for transplant recipients, including patients undergoing hematopoietic stem cell transplantation (HSCT). Interestingly, several studies have reported an association between early CMV reactivation and a reduced risk of leukemia relapse, particularly in acute myeloid leukemia (AML). Given that CMV profoundly shapes the natural killer (NK) cell compartment, a contribution of CMV-primed NK cells to this effect has been proposed. To explore this mechanism, we analyzed the relationship between NK cell functionality and CMV reactivation in the context of AML. Consistent with observations in peripheral blood, CMV-seropositive HSCT recipients displayed expanded NKG2Cpos NK cell populations within the bone marrow, characterized by high Granzyme B expression. CMV replication was associated with elevated plasma IFN{gamma} levels, which in vitro rendered AML cells more susceptible to apoptosis when co-cultured with peripheral blood mononuclear cells. Importantly, IFN{gamma} treatment modulated NK cell responses by inducing a variety of NK cell ligands including HLA-E on primary bone marrow-derived blasts and AML cell lines. In line with this, the activation of CMV-associated NKG2Cpos NK cells was enhanced upon stimulation with IFN{gamma}-pretreated AML cells. In summary, our findings demonstrate that CMV replication induces a transient increase in IFN{gamma} levels that influences both AML and NK cells, ultimately enhancing AML cell susceptibility to NK cell-mediated cytotoxicity initiated through the NKG2C-HLA-E axis. ImportancePrevious studies suggested that CMV reactivation after HSCT may reduce leukemia relapse in AML patients, but the underlying mechanism remained unclear. Here, we show that CMV replication induces IFN{gamma} release, which sensitizes AML cells to NK cell-mediated killing. This effect involves upregulation of HLA-E on AML cells and activation of expanded NKG2Cpos NK cells within the bone marrow. Our findings uncover a novel IFN{gamma}-dependent link between CMV replication and enhanced NK cell cytotoxicity in AML, suggesting that combining IFN{gamma} treatment with NK cell-based immunotherapy or NKG2A blockade could reduce post-HSCT relapse, even in CMV-negative patients.

immunology↗

bioRxiv2025

The mycotoxin Beauvericin is an uncompetitive inhibitor of Cathepsin B

Beauvericin (BEA), a cyclic depsipeptide, is a mycotoxin of the enniatin family and the secondary metabolite of various toxigenic fungi. Multiple biological functions of BEA have been well investigated, such as anti-cancer, anti-inflammatory, anti-microbial, and immune-activating functions. In a recent study, we showed that BEA can target Toll-like receptor 4 (TLR4) to induce dendritic cell (DC) activation. In an in silico screen, we identified Cathepsin B (CTSB) as a potential additional interaction partner for BEA, which has been verified recently in a study showing inhibition of CTSB activity by BEA in cell-free assays. The underlying molecular mechanism of BEA-mediated CTSB inhibition remains unknown as do the cellular entities where this inhibition takes place. In this study, we determine the effects of BEA on CTSB within granulocyte-macrophage colony-stimulating factor (GM-CSF)-cultured bone marrow-derived dendritic cells (BMDCs) and human leukemia monocytic cell line THP-1 induced dendritic cells (iDCs). BEA significantly suppresses CTSB activity in both mouse BMDCs and human iDCs. NMR analyses indicate that BEA directly interacts with CTSB. Enzyme kinetics show that BEA can directly inhibit CTSB activity and acts as an uncompetitive inhibitor. Molecular docking analysis revealed a putative binding site for BEA in human CTSB. Collectively, we describe the molecular mechanisms underlying the biological activity of BEA against human CTSB, suggesting that CTSB may be a candidate target for tumor therapy.

biochemistry↗

bioRxiv2024

SARS-CoV-2 modulates NK cell responses via induction of HLA-E and triggers expansion of adaptive NK cells during acute infection

HLA-E expression plays a central role for modulation of NK cell function by interaction with inhibitory NKG2A and stimulatory NKG2C receptors on canonical and adaptive NK cells, respectively. Here, we demonstrate that infection of human primary lung tissue with SARS-CoV-2 leads to increased HLA-E expression and show that processing of the peptide YLQPRTFLL from the spike protein is primarily responsible for the strong, dose-dependent increase of HLA-E. Targeting the peptide site within the spike protein revealed that a single point mutation was sufficient to abrogate the increase in HLA-E expression. Spike-mediated induction of HLA-E differentially affected NK cell function: whereas degranulation, IFN-{gamma} production, and target cell cytotoxicity were enhanced in NKG2C+ adaptive NK cells, effector functions were inhibited in NKG2A+ canonical NK cells. Analysis of a cohort of COVID-19 patients in the acute phase of infection revealed that adaptive NK cells were induced irrespective of the HCMV status, challenging the paradigm that adaptive NK cells are only generated during HCMV infection. During the first week of hospitalization, patients exhibited a selective increase of early NKG2C+CD57- adaptive NK cells whereas mature NKG2C+CD57+ cells remained unchanged. Further analysis of recovered patients suggested that the adaptive NK cell response is primarily driven by a wave of early adaptive NK cells during acute infection that wanes once the infection is cleared. Together, this study suggests that NK cell responses to SARS-CoV-2 infection are majorly influenced by the balance between canonical and adaptive NK cells via the HLA-E/NKG2A/C axis.

immunology↗

bioRxiv2022

The mycotoxin Beauvericin exhibits immunostimulatory effects on dendritic cells via activating the TLR4 signaling pathway

Beauvericin (BEA), a mycotoxin of the enniatin family produced by various toxigenic fungi, has been attributed multiple biological activities such as anti-cancer, anti-inflammatory, and anti-microbial functions. However, effects of BEA on dendritic cells remain unknown so far. Here, we identified effects of BEA on murine granulocyte-macrophage colony-stimulating factor (GM-CSF)-cultured bone marrow derived dendritic cells (BMDCs) and the underlying molecular mechanisms. BEA potently activates BMDCs as signified by elevated IL-12 and CD86 expression. Multiplex immunoassays performed on myeloid differentiation primary response 88 (MyD88) and toll/interleukin-1 receptor (TIR) domain containing adaptor inducing interferon beta (TRIF) single or double deficient BMDCs indicate that BEA induces inflammatory cytokine and chemokine production in a MyD88/TRIF dependent manner. Furthermore, we found that BEA was not able to induce IL-12 or IFN{beta} production in Toll-like receptor 4 (Tlr4)-deficient BMDCs, whereas induction of these cytokines was not compromised in Tlr3/7/9 deficient BMDCs. This suggests that TLR4 might be the functional target of BEA on BMDCs. Consistently, in luciferase reporter assays BEA stimulation significantly promotes NF-{kappa}B activation in mTLR4/CD14/MD2 overexpressing but not control HEK-293 cells. RNA-sequencing analyses further confirmed that BEA induces transcriptional changes associated with the TLR4 signaling pathway. Together, these results identify TLR4 as a cellular BEA sensor and define BEA as a potent activator of BMDCs, implying that this compound can be exploited as a promising candidate structure for vaccine adjuvants or cancer immunotherapies.

immunology↗

bioRxiv2020

Umbilical cord blood-derived ILC1-like cells constitute a novel precursor for mature KIR+NKG2A- NK cells

Despite their identification several years ago, molecular identity and developmental relation between human ILC1 and NK cells, comprising group 1 ILCs, is still elusive. To unravel their connection, thorough transcriptional, epigenetic, and functional characterization was performed from umbilical cord blood (CB). Unexpectedly, ILC1-like cells lacked Tbet expression and failed to produce IFNg. Moreover, in contrast to previously described ILC1 subsets they could be efficiently differentiated into NK cells. These were characterized by highly diversified KIR repertoires including late stage NKG2A-KIR+ effector cells that are commonly not generated from previously known NK cell progenitor sources. This property was dependent on stroma cell-derived Notch ligands. The frequency of the novel ILC1-like NK cell progenitor (NKP) significantly declined in CB from early to late gestational age. The study supports a model in which circulating fetal ILC1-like NKPs travel to secondary lymphoid tissues to initiate the formation of diversified NK cell repertoires after birth.

immunology↗