Inflammation-induced lactate leads to the rapid loss of hepatic tissue resident NK cells

Abstract

Abstract The liver harbors two main innate lymphoid cell (ILC) populations, conventional NK (cNK) cells and tissue-resident NK (trNK) cells also called ILC1s. While the antiviral functions of cNK cells have been well established, trNK cell functions are only beginning to be uncovered. Using the MCMV model of infection, we found that in contrast to liver cNK cells, the trNK cell population initially undergoes a contraction phase prior to a recovery phase to homeostatic levels. The rapid contraction phase is due to apoptosis, while the recovery phase occurs via proliferation in situ. Liver trNK cell apoptosis is not mediated by fratricide, liver lymphocytes, or inflammatory cytokines. Instead, we found that liver trNK cell apoptosis is the consequence of an increased sensitivity to lactic acid. Interestingly, MCMV infection lead to an increase of lactate in the liver, which was supported by changes in lactate dehydrogenase expression. Mechanistic analysis indicates that trNK cell sensitivity to lactate is linked to impaired mitochondrial functions. These findings underscore the unique properties of the liver resident NK cell compartment.