MyD88 is an essential regulator of NK cell-mediated clearance of MCMV infection

Dixon, Kate; Siebert, Jason R.; Wang, Dandan; Abel, Alex M.; Johnson, Kaitlin E.; Riese, Matthew J.; Terhune, Scott S.; Tarakanova, Vera L.; Thakar, Monica S.; Malarkannan, Subramaniam

doi:10.1016/j.molimm.2021.07.001

Cited by 6 publications

(5 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to previous studies(61), we too observed increased activation among several NK subsets in the PHIV cohort. These cells had increased expression of activation markers such as CD69, NKp44 and HLA-DR in many NK subpopulations, and bulk RNA-seq data confirmed upregulated transcription of signaling adaptors like MyD88 which is critical for NK and other immune cell activation(62) along with enriched GO terms like ‘NK cell activation involved in immune response’.…”

Section: Discussionmentioning

confidence: 84%

Activated NK Cells with Pro-inflammatory Features are Associated with Atherogenesis in Perinatally HIV-Acquired Adolescents

Alles,

Gunasena,

Kettelhut

et al. 2023

Preprint

View full text Add to dashboard Cite

Human immunodeficiency virus (HIV) is associated with persistent immune activation and dysfunction in people with HIV despite treatment with antiretroviral therapy (ART). Modulation of the immune system may be driven by: low-level HIV replication, co-pathogens, gut dysbiosis /translocation, altered lipid profiles, and ART toxicities. In addition, perinatally acquired HIV (PHIV) and lifelong ART may alter the development and function of the immune system. Our preliminary data and published literature suggest reprogramming innate immune cells may accelerate aging and increase the risk for future end-organ complications, including cardiovascular disease (CVD). The exact mechanisms, however, are currently unknown. Natural killer (NK) cells are a highly heterogeneous cell population with divergent functions. They play a critical role in HIV transmission and disease progression in adults. Recent studies suggest the important role of NK cells in CVDs; however, little is known about NK cells and their role in HIV-associated cardiovascular risk in PHIV adolescents. Here, we investigated NK cell subsets and their potential role in atherogenesis in PHIV adolescents compared to HIV-negative adolescents in Uganda. Our data suggest, for the first time, that activated NK subsets in PHIV adolescents may contribute to atherogenesis by promoting plasma oxidized low-density lipoprotein (Ox-LDL) uptake by vascular macrophages.

show abstract

Section: Discussionmentioning

confidence: 84%

Activated NK Cells with Pro-inflammatory Features are Associated with Atherogenesis in Perinatally HIV-Acquired Adolescents

Alles,

Gunasena,

Kettelhut

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…This analysis revealed that interactions between monocytes and NK cells in severe COVID-19 were predicted to upregulate genes involved in NK cell cytotoxicity [ GZMB ( 48 ), PRF1 ( 49 ), LGALS1 ( 50 ), TNFSF10 ( 51 )], proliferation [ MCM6 ( 52 ), KNTC1 ( 53 )], apoptosis [ ANXA2 ( 54 ), ANXA5 ( 54 ), BAX ( 55 ), FAS ( 56 ), CASP1 ( 57 ), PML ( 58 )], cellular adhesion [ STMN1 ( 59 ), VCAN ( 35 )], and migration [ CX3CR1 ( 60 )]. Other predicted downstream targets in severe COVID-19 included several genes associated with decreased NK cell functionality [ EZH2 ( 61 ), PRDM1 ( 62 ), SERPINB1 ( 63 )], two STAT family transcription factors [ STAT1 , STAT2 ( 64 )], and signaling adaptor MYD88 ( 65 ) ( Fig. 2C ).…”

Section: Resultsmentioning

confidence: 99%

NK Cell–Monocyte Cross-talk Underlies NK Cell Activation in Severe COVID-19

Lee,

de los Rios Kobara,

Barnard

et al. 2024

The Journal of Immunology

View full text Add to dashboard Cite

NK cells in the peripheral blood of severe COVID-19 patients exhibit a unique profile characterized by activation and dysfunction. Previous studies have identified soluble factors, including type I IFN and TGF-β, that underlie this dysregulation. However, the role of cell–cell interactions in modulating NK cell function during COVID-19 remains unclear. To address this question, we combined cell–cell communication analysis on existing single-cell RNA sequencing data with in vitro primary cell coculture experiments to dissect the mechanisms underlying NK cell dysfunction in COVID-19. We found that NK cells are predicted to interact most strongly with monocytes and that this occurs via both soluble factors and direct interactions. To validate these findings, we performed in vitro cocultures in which NK cells from healthy human donors were incubated with monocytes from COVID-19+ or healthy donors. Coculture of healthy NK cells with monocytes from COVID-19 patients recapitulated aspects of the NK cell phenotype observed in severe COVID-19, including decreased expression of NKG2D, increased expression of activation markers, and increased proliferation. When these experiments were performed in a Transwell setting, we found that only CD56bright CD16− NK cells were activated in the presence of severe COVID-19 patient monocytes. O-link analysis of supernatants from Transwell cocultures revealed that cultures containing severe COVID-19 patient monocytes had significantly elevated levels of proinflammatory cytokines and chemokines, as well as TGF-β. Collectively, these results demonstrate that interactions between NK cells and monocytes in the peripheral blood of COVID-19 patients contribute to NK cell activation and dysfunction in severe COVID-19.

show abstract

“…This discrepancy might be explained by the complex crosstalk of multiple signaling pathways from cytokine and/or activating receptors during MCMV infection [15,16,18]. In addition, MCMV susceptibility is highly increased in mice deficient in MyD88 or Trif [37][38][39][40]. Thus, excessive inflammation associated with increased MCMV susceptibility might induce TNFR2 upregulation on NK cells from cytokines and/or infected cells, which may compensate for IL-18-MyD88 signaling.…”

Section: Discussionmentioning

confidence: 99%

The TNFα/TNFR2 axis mediates natural killer cell proliferation by promoting aerobic glycolysis

et al. 2023

View full text Add to dashboard Cite

Natural killer (NK) cells are predominant innate lymphocytes that initiate the early immune response during infection. NK cells undergo a metabolic switch to fuel augmented proliferation and activation following infection. Tumor necrosis factor-alpha (TNFα) is a well-known inflammatory cytokine that enhances NK cell function; however, the mechanism underlying NK cell proliferation in response to TNFα is not well established. Here, we demonstrated that upon infection/inflammation, NK cells upregulate the expression of TNF receptor 2 (TNFR2), which is associated with increased proliferation, metabolic activity, and effector function. Notably, IL-18 can induce TNFR2 expression in NK cells, augmenting their sensitivity toward TNFα. Mechanistically, TNFα-TNFR2 signaling upregulates the expression of CD25 (IL-2Rα) and nutrient transporters in NK cells, leading to a metabolic switch toward aerobic glycolysis. Transcriptomic analysis revealed significantly reduced expression levels of genes involved in cellular metabolism and proliferation in NK cells from TNFR2 KO mice. Accordingly, our data affirmed that genetic ablation of TNFR2 curtails CD25 upregulation and TNFα-induced glycolysis, leading to impaired NK cell proliferation and antiviral function during MCMV infection in vivo. Collectively, our results delineate the crucial role of the TNFα-TNFR2 axis in NK cell proliferation, glycolysis, and effector function.

show abstract

MyD88 is an essential regulator of NK cell-mediated clearance of MCMV infection

Cited by 6 publications

References 92 publications

Activated NK Cells with Pro-inflammatory Features are Associated with Atherogenesis in Perinatally HIV-Acquired Adolescents

Activated NK Cells with Pro-inflammatory Features are Associated with Atherogenesis in Perinatally HIV-Acquired Adolescents

NK Cell–Monocyte Cross-talk Underlies NK Cell Activation in Severe COVID-19

The TNFα/TNFR2 axis mediates natural killer cell proliferation by promoting aerobic glycolysis

Contact Info

Product

Resources

About