Natural Killer (NK) cells are a major component of host immunity against viral infections, rapidly responding to infected cells by secreting cytokines and lytic granules. Using a well-established mouse cytomegalovirus (MCMV) infection model, our lab and others have demonstrated that NK cells undergo dynamic metabolic and epigenetic shifts during antiviral responses to fuel their activation and effector functions. However, the mechanisms by which NK cells coordinate these metabolic and epigenetic changes are not well understood. 

Growing evidence indicates that central metabolites play important roles in immune cell activation by acting not only as energy sources but also as substrates for growth signaling pathways, epigenetic regulation, and effector differentiation. L-2-hydroxyglutarate (L-2HG) is an immunometabolite that has been shown to play a role in coordinating metabolic and epigenetic shifts in activated CD8⁺ T cells, dendritic cells, and macrophages. During activation, L-2HG accumulates and acts as a potent competitive inhibitor of ⍺KG-dependent enzymes, including histone lysine demethylases and hypoxia inducible factor prolyl hydroxylases, altering the epigenetic and metabolic state of these cells. While L-2HG has been shown to be relevant in other immune responses, the role of L-2HG in NK cells is unknown. RNA-seq data from a time course of MCMV infection reveal a peak in the expression of L-2HG dehydrogenase (which specifically metabolizes L-2HG) in NK cells on day 2 post infection, suggesting that NK cells carefully control L-2HG levels early during activation. Ncr1^Cre-L2hgdh^fl/fl mice (L2HKO) with NK cell-specific L-2HG accumulation have significantly reduced survival during high dose MCMV infection compared to littermate controls. In addition, L2HKO NK cells demonstrate an expansion defect in adoptive co-transfer experiments. Preliminary evidence suggests that L-2HG in NK cells may increase HIF-1⍺ activity. Ongoing studies aim to elucidate the epigenetic and metabolic pathways influenced by L-2HG in NK cells during MCMV infection.