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Uncovering mechanisms of NK cell metabolic reprogramming during viral infection

Posted: September 24, 2021

Written by: Elizabeth Balint and Ana Portillo

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In their newest Frontiers in Immunology publicationDr. Abrar Khan, Saeedah Almutairi, and Dr. Seung-Hwan Lee investigate mechanisms of NK cell metabolic reprogramming during MCMV infection.

Cellular metabolism has recently emerged as a fundamental regulator of immune cell effector function. In response to inflammatory stimuli, such as viral infection, NK cells undergo metabolic reprogramming to support their proliferation and activation. For example, to meet higher energy demands of augmented proliferation, NK cells exhibit enhanced mTOR activity, upregulated expression of nutrient transport receptors, and increased mitochondrial mass.


NK cell activation and effector function is dependent on signaling from both cytokines and engagement of activation/inhibitory receptors. The IL-1 family of inflammatory cytokines, such as IL-18 and IL-33, are essential for NK cell activation. Specifically, IL-18 upregulates NK cell proliferation and function via MyD88-mediated activation of NF-κB. Furthermore, IL-18 signaling drives the expansion of NK cells expressing the Ly49H, an activation receptor during murine cytomegalovirus (MCMV) infection. Upregulation of the iron transporter CD71 and amino acid transporter CD98, has been correlated with heightened NK cell function after ex vivo IL-18 stimulation. However, the role of IL-1 family cytokines in regulating NK cell metabolism during viral infection in vivo was previously unknown.


Using MCMV as a model for viral infection, Khan et al. investigated how signaling of IL-1 family cytokines through MyD88 regulates the expression of nutrient transporters on activated NK cells. The authors first demonstrated a correlation between proliferation and the expression of nutrient receptors (CD71 and CD98) on NK cells during MCMV infection. Similarly, administration of recombinant IL-18 in mice increased proliferation and nutrient transporter expression on NK cells.


To specifically identify the role of IL-18 signaling on NK cell nutrient transporter expression, authors generated a novel NK cell-specific IL-18 receptor-deficient mouse model. Surprisingly, MCMV infection of these mice did not alter the expression of CD71 and CD98, suggesting that IL-18 signaling is dispensable during MCMV infection and does not directly mediate metabolic reprogramming in NK cells. However, using MyD88 knockout mice, the authors determined that nutrient transporter expression is regulated in a MyD88-dependent manner. Supporting this, Khan et al. found that IL-33, another member of IL-1 family cytokine signaling through MyD88, and IL-12 synergistically upregulate the expression of nutrient transporters. Lastly, they show that engagement of the Ly49H activation receptor also contributes to the increased nutrient transporter expression, which is further enhanced by IL-18 signaling.


Overall, these results demonstrate that multiple pathways, involving both cytokines and activating receptors, trigger metabolic reprogramming of NK cells to support their proliferation and effector function during infection. Further investigation of mechanisms that govern NK cell metabolism and function may provide novel avenues for NK cell therapies against cancer and viral infections, particularly in the nutrient-deprived and immunosuppressive tumor microenvironment.

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