Potentiating Immune Cells Function During Inflammation and Virus Infection by Modulating Metabolism

Abstract

Natural killer cells are innate lymphocytes that provide antiviral immunity. Resting NK cells oxidize glucose, lipids, and amino acids to generate ATP, which is essential to help the cells maintain their normal functions during immune surveillance. During inflammation and infection, NK cells shift their metabolism and upregulate their nutrient receptors such as glucose, amino acid, and iron transporters, while activating mTORC1 to produce the biosynthetic precursors that are required for cell growth, proliferation, and cytokines secretion. I identified that IL-18 is a potent cytokine which regulates NK cell metabolism and enhances their proliferation by increasing the expression of nutrient receptors and induce leucine-driven mTORC1 activation. During infection, immune cells are subjected to cellular stresses, and these stresses are regulated by the redox state, which influences cell growth, metabolism, and death. Glrx2 is an enzyme of the antioxidant system that controls ROS production. I used Glrx2-deficient mice as a model to study the effect of ROS on immune cell development, IFN production, cytotoxic potential, and proliferation in the naïve mice and in mice upon acute and persistent MCMV infection. By targeting the antioxidant system and the IL-18 pathway during infection, my study will open up new avenues for therapeutic applications in enhancing natural killer and T cell functions for immunotherapy.