LAG3 marks activated but hyporesponsive NK cells

Natural Killer (NK) cells are critical for immunosurveillance. However, NK cells can become dysfunctional in contexts such as chronic stimulation by viral infections or cancer. NK cells often display an increased expression of immune checkpoint proteins (ICP) following chronic stimulation, and ICP blockade therapies are currently being explored for several cancer types, which have remarkable patient benefits. Nevertheless, the nature of ICP expression in NK cells is still poorly documented. In this study, we aimed to identify the phenotype of immune checkpoint LAG3 (Lymphocyte-activation gene 3) expressing NK cells. Using various experimental models (inflammation triggered by poly (I:C), cytokine treatment, Eµ-myc spontaneous lymphoma model and MCMV infection), we found that LAG3 is expressed by murine NK cells upon activation in different contexts, including in response to cancer and acute viral infections. We then sought to define the molecules features of NK cells expressing LAG3. LAG3 marks a subset of immature, proliferating and activated cells, which, despite activation, have a reduced capacity to respond to a broad range of stimuli. Further characterization also revealed that LAG3+ NK cells exhibit a transcriptional signature similar to that of exhausted CD8+ T cells. Taken together, our results support the use of LAG3 as a marker of dysfunctional NK cells across diverse chronic and acute inflammatory conditions.