CD49a expression defines a metabolically robust, cytokine‐biased liver NK cell subset in rhesus macaques during lentivirus infection

Abstract Liver‐resident natural killer (LrNK) cells are critical regulators of hepatic immune homeostasis and demonstrate antiviral activity, yet their role in lentivirus infections remains poorly defined. Using a rhesus macaque (RM) model of Simian immunodeficiency virus (SIV) and Simian‐human immunodeficiency virus (SHIV) infections, we investigated the phenotypes, metabolic profiles and functional responses of hepatic NK cells across naïve, acutely SIV‐infected and chronically SHIV‐infected RM. We identified liver‐resident (Lr) NK cells as CD3−CD159a/c+CD49a+, whereas CD3−CD159a/c+CD49a− NK cells include circulating NK cell subsets in the liver. Across infection states, CD49a+ LrNK cells exhibited elevated expression of activation markers, including NKG2D, NKp30, NKp46 and CD69, as well as increased expression of metabolic markers, including CD98, Glut1 and MitoTracker. In contrast, Ki‐67 expression was reduced in CD49a+ LrNK cells compared with their CD49a− counterparts. Unsupervised clustering revealed that CD49a+ LrNK cells were also marked by high CD69 expression. While total NK cell cytokine secretion was elevated in acute SIV‐infected animals, CD49a+ LrNK cells exhibited robust polyfunctional cytokine responses and reduced expression of the cytotoxic marker CD107a upon mitogen stimulation in comparison with CD49a− LrNK cells regardless of infection status. These findings reveal distinct metabolic and functional specialization of hepatic NK cell subsets, underscoring the unique phenotype and functions of CD49a+ LrNK cells in RM, which may offer novel insights and therapeutic opportunities for treating liver inflammation in HIV infection and other chronic liver diseases.