Liver-resident NK cells suppress autoimmune cholangitis and limit the proliferation of CD4^(+) T cells

Liver-resident NK cells are distinct from conventional NK cells and play an important role in the maintenance of liver homeostasis.How liver-resident NK cells participate in autoimmune cholangitis remains unclear.Here,we extensively investigated the impact of NK cells in the pathogenesis of autoimmune cholangitis utilizing the well-established dnTGFβRII cholangitis model,NK cell-deficient(Nfil3−/−)mice,adoptive transfer and in vivo antibody-mediated NK cell depletion.Our data demonstrated that disease progression was associated with a significantly reduced frequency of hepatic NK cells.Depletion of NK cells resulted in exacerbated autoimmune cholangitis in dnTGFβRII mice.We further confirmed that the DX5−CD11c^(hi) liver-resident NK cell subset colocalized with CD4^(+) T cells and inhibited CD4^(+) T cell proliferation.Gene expression microarray analysis demonstrated that liver-resident NK cells had a distinct gene expression pattern consisting of the increased expression of genes involved in negative regulatory functions in the context of the inflammatory microenvironment.

Asialo GM1-positive liver-resident CD8 T cells that express CD44 and LFA-1 are essential for immune clearance of hepatitis B virus

Persistent hepatitis B virus(HBV)infection results in chronic liver diseases that may progress to chronic hepatitis,liver cirrhosis,and subsequent hepatocellular carcinoma.Previous studies demonstrated that adaptive immunity,in particular CD8 T cells,is critical in HBV elimination.Recent studies have revealed a distinct tissue-localized T cell lineage,tissue-resident memory(TRM)cells,that is crucial for protective immunity in peripheral tissues.In this study,we showed that treatment with an anti-asialo GM1(ASGM1)antibody(Ab),which depletes NK cells,led to impairment of HBV clearance in a mouse animal model.Unexpectedly,the ability to clear HBV was not significantly impaired in NFIL3 KO mice,which are deficient in NK cells,implying that other non-NK ASGM1-positive immune cells mediate HBV clearance.We isolated intrahepatic ASGM1-positive cells from NFIL3 KO mice and analyzed the immune phenotype of these cells.Our results demonstrated a distinct population of CD44+LFA-1hi CD8 T cells that were the major intrahepatic ASGM1-positive immune cells in NFIL3 KO mice.Importantly,transcriptome analysis revealed that these ASGM1-positive CD8 T cells had distinct gene profiles and shared a similar core gene signature with TRM cells.In addition to both transcriptional and phenotypic liver residency characteristics,ASGM1-positive CD8 T cells were able to home to and be retained in the liver after adoptive transfer.Taken together,our study results indicate that these ASGM1-positive liver-resident CD8 T cells are the major effector immune cells mediating anti-HBV immunity.

Liver natural killer cells： subsets and roles in liver immunity

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 ceils 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,