Liver natural killer cells: subsets and roles in liver immunity

Abstract

The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply. With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer (NK) cells play important roles in host defense and in maintaining immune balance. Hepatic NK cells were first described as ‘pit cells' in the rat liver in the 1970s. Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK (cNK) cells, are present in this organ. Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit cells and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity.

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

“…For example, although many strategies and technologies have been presented to improve therapeutic efficacy, the outcomes of CAR-NK cell immunotherapy remain unpredictable, especially in solid tumors. Due to the heterogeneity of NK cells, which contain different NK subsets with different functional features [86][87][88][89] , the need to select suitable NK cell subsets (eg, killer subpopulation) to selectively expand and construct specific CAR-NK cells is yet to be explored. Are naïve or memorylike NK cells better for expansion and transduction?…”

Cutting Edge: Human CD49e− NK Cells Are Tissue Resident in the Liver

“…However, it is likely that liver trNK cells may be especially important due to their location. More data are available in rodents, indicating that trNK cells reside in the liver sinusoids where they should be better positioned to deal with intravascular tumors and pathogens as well as interact with Kupffer cells (21). Since we identified CD49e − NK cells in L-PxF samples, it is very likely that human trNK cells are also selectively in the sinusoids.…”

NK cell education via nonclassical MHC and non-MHC ligands

“…80, 83, 84 Similarly, when potential targets, for example, autoreactive T cells or tumor cells, maintain a high expression of nonclassical MHC Qa-1 or HLA-E, NKG2A-mediated education is not beneficial for NK cell effector function and conversely inhibits NK cell responses. 85, 86, 87 Furthermore, the high expression of ligands specific for non-MHC inhibitory receptors, once engaged, triggers dominant negative signals to inhibit NK cell reactivity. The Clr-b-NKRP1-B axis, as an example, is critical for the immune escape of spontaneous myc-induced B lymphomas.…”