Expression of Nutrient Transporters on NK Cells during Murine Cytomegalovirus Infection is MyD88-Dependent

Abstract Natural killer (NK) cells are the predominant innate lymphocytes that provide the first line of defence without prior sensitization. In the inflammatory milieu, NK cells modify their metabolism to cope with the high energy demand required to support their proliferation, activation, and functional plasticity. This metabolic reprogramming is usually accompanied by the upregulated expression of nutrient transporters on the cell surface, leading to increased nutrient uptake needed for robust proliferation. The members of interleukin-1 family of inflammatory cytokines are critical in activating NK cells during infection; however, their function in NK cell metabolism is not fully elucidated. Previously, IL-18 has been shown to upregulate the expression of solute carrier transmembrane proteins and thereby induces a robust metabolic boost in NK cells. However, we demonstrated that IL-18 signaling is dispensable during viral infection in vivo whereas the expression of nutrient transporters on NK cells is primarily regulated by MyD88-pathway since NK cells from Myd88−/− mice displayed significantly reduced expression of nutrient receptors. Moreover, we identified that IL-33, another cytokine employing MyD88 signaling, can induce the expression of nutrient receptor but requires a sequential exposure to IL-12. Furthermore, signaling through NK cells activating receptor, Ly49H, can also promote the expression of nutrient transporters. In summary, our findings revealed multiple pathways that induce the expression of nutrient transporters on NK cells while highlighting the imperative role of MyD88 in NK cell metabolism during infection.