Regulation of NK cell repertoire and function in the liver

Abstract

NK cells represent a large proportion of the lymphocyte population in the liver and are involved in early innate immunity to pathogen infection. As a result of liver endothelial cell fenestrations, parenchymal cells are not separated by a basal membrane, and thereby pathogen-infected hepatocytes are extensively capable of interacting with innate immune cells including NK cells. In addition, hepatic NK cells interact with surrounding DC and alter their differentiation and function. Recent studies reveal that NK cells exhibit a regulatory function that modulates T cell responses through their interaction with DC and/or direct effect on T cells. Thus, NK cells play a central role, not only in innate immunity, but also in shaping the adaptive immune response. During pathogen infection, there is a remarkable increase of hepatic NK cells, possibly due to the expansion of resident liver NK cells and/or recruitement of NK cells from the blood. The liver microenvironment is believed to modulate hepatic NK cell function through the induction of activating/inhibitory receptor expression and inflammatory cytokine secretion. Particularly, the liver maintains intrahepatic NK cells in a functionally hyporesponsive state compared to splenic NK cells: liver NK cells displayed a dampened IFN-γ response to IL-12/IL-18 stimulation. Notably, the liver contains a significant population of functionally hyporesponsive NK cells that express high levels of the inhibitory receptor NKG2A and lack expression of MHC class I-binding Ly49 receptors. Importantly, adoptively transferred splenic NK cells that migrate to the liver displayed phenotypic and functional changes, supporting a view that the liver environment modifies NK cell receptor expression and functional responsiveness. In this article, we will review studies on the regulation of NK cell repertoire and function in the hepatic environment and the impact of liver NK cell immunoregulatory function on influencing adaptive immunity.

FIGURE 1. NK cell education models

Models for NK cell education include the arming, the disarming, and the rheostat paradigms. Arming model indicates that a direct signaling through a MHC-I binding inhibitory receptor conveys functional capacity to the NK cell. Disarming model suggests that in the absence of inhibitory signaling while receiving an activating stimulus, NK cells will progress to hyporesponsivity. Rheostat model suggests that the strength of one or many inhibitory signals leads to NK cell functionality, where stronger inhibition correlates to higher INF-g production. (Modified from Hoglund and Brodin, Nature Reviews Immunology 2010).

FIGURE 2. NK cell activating/inhibitory receptors and other surface molecules

Numerous molecules including activating/inhibitory receptors and cytotoxicity receptors are expressed on the cell surface of NK cells and participate in acquiring NK cell effector function. The inhibitory receptors (−) are depicted as red with long intracellular protein domains; the activating receptors (+) are presented as blue with short intracellular protein domains. Both human and mouse NK cells express the inhibitory receptor NKG2A, and the activating receptors NKG2D, NKp46 and CD16. Moreover, 2B4 and NKRP1 are involved in the signaling to trigger NK cell development, and can induce either inhibitory or activating signals. While human NK cells have 15 inhibitory and activating KIR receptors, mouse NK cells contain at least 19 inhibitory and activating Ly49 receptors. The human natural cytotoxicity receptors (NCR) NKp30, NKp44, and NKp46 are all activating receptors that induce NK cell cytolytic function upon cell-cell contact.

FIGURE 3. Immunoregulatory role of NK cells

NK cells play a role in shaping adaptive immune responses by either NK-DC interaction or direct effect on T cells. NK-DC crosstalk is implicated in the potential for DC's ability to successfully prime T cells. Cytokines from both NK cells and DC counter-regulate each other, resulting in affecting T cell function. Furthermore, NK cells exhibit direct cytolytic function toward both DC and T cells ex vivo.