Inflammation-Induced Lactate Leads to Rapid Loss of Hepatic Tissue-Resident NK Cells

The liver harbors two main innate lymphoid cell (ILC) populations: conventional NK (cNK) cells and tissue-resident NK (trNK) cells. Using the MCMV model of infection, we find that, in contrast to liver cNK cells, trNK cells initially undergo a contraction phase followed by a recovery phase to homeostatic levels. The contraction is MCMV independent because a similar phenotype is observed following poly(I:C)/CpG or α-GalCer injection. The rapid contraction phase is due to apoptosis, whereas the recovery phase occurs via proliferation in situ. Interestingly, trNK cell apoptosis is not mediated by fratricide and not induced by liver lymphocytes or inflammatory cytokines. Instead, we find that trNK cell apoptosis is the consequence of an increased sensitivity to lactic acid. Mechanistic analysis indicates that trNK cell sensitivity to lactate is linked to impaired mitochondrial function. These findings underscore the distinctive properties of the liver-resident NK cell compartment. [Display omitted] •Hepatic conventional NK and tissue-resident NK cells differ in kinetic response to MCMV•Hepatic trNK cells undergo rapid apoptosis during liver inflammation•trNK cell apoptosis is due to lactate sensitivity and impaired mitochondrial function In this study, Dodard et al. evaluate the kinetics of the liver NK cell compartment in response to viral infection. They show that, in contrast to conventional NK cells, tissue-resident NK cells undergo apoptosis, which is due to a higher sensitivity to lactic acid and impaired mitochondrial function.