NKG2A and the functional competence of liver natural killer cells

Abstract

The liver is a unique environment that maintains tolerance to a heavy load of foreign antigens derived from the intestine. The liver is also the site of several chronic viral infections, including hepatitis B & C viruses. Defining the mechanism(s) underlying the tolerogenic environment of the liver will broaden our understanding of normal liver function and contribute to better therapeutic strategies to persistent infection. Natural killer cells (NKs) make up a large percentage of the liver lymphocyte population. NKs play a critical role in innate immunity and generating adaptive immunity via crosstalk with dendritic cells (DCs). To determine the role of liver NK cells in modulating host immunity, we examined cytokine production upon interaction of NKs with DCs. When liver or spleen NKs were co‐cultured with splenic DC in the presence of IL‐12 or IL‐15, IFN‐γ was significantly decreased in the liver NK‐DC coculture compared to the spleen NK‐DC coculture, in the presence of either IL‐12 or IL‐15. We next determined the status of NK cell differentiation and the expression of both inhibitory and activating NK receptors in the liver and spleen on specific NK subsets defined by the expression of CD27 and CD11b. The inhibitory receptor NKG2A was expressed at higher levels on liver NKs compared to spleen NKs. This higher expression was observed in all NK subsets, but most pronounced in the CD27highCD11blow subset. In contrast, expression within all subsets of the activating receptor NKG2D, as well as all Ly49 receptors, was lower on liver NKs compared to spleen NKs. These results suggest that the liver NK cell may be less functionally competent than spleen NK cells, and that the inhibitory receptor NKG2A may play a prominent role in the effector status of NKs within the liver.