Intrahepatic and peripheral blood phenotypes of natural killer and T cells: differential surface expression of killer cell immunoglobulin‐like receptors

Abstract

Deep characterization of the frequencies, phenotypes and functionalities of liver and peripheral blood natural killer (NK), natural killer T (NKT) and T cells from healthy individuals is an essential step to further interpret changes in liver diseases. These data indicate that CCR7, a chemokine essential for cell migration through lymphoid organs, is almost absent in liver NK and T cells. CD56 NK cells, which represent half of liver NK cells, showed lower expression of the inhibitory molecule NKG2A and an increased frequency of the activation marker NKp44. By contrast, a decrease of CD16 expression with a potential decreased capacity to perform antibody-dependent cellular cytotoxicity was the main difference between liver and peripheral blood CD56 NK cells. Liver T cells with an effector memory or terminally differentiated phenotype showed an increased frequency of MAIT cells,T-cell receptor-γδ (TCR-γδ) T cells and TCR-αβ CD8 cells, with few naive T cells. Most liver NK and T cells expressed the homing markers CD161 and CD244. Liver T cells revealed a unique expression pattern of killer cell immunoglobulin-like receptors (KIR) receptors, with increased degranulation ability and higher secretion of interferon-γ. Hence, the liver possesses a large amount of memory and terminally differentiated CD8 cells with a unique expression pattern of KIR activating receptors that have a potent functional capacity as well as a reduced amount of CCR7, which are unable to migrate to regional lymph nodes. These results are consistent with previous studies showing that liver T (and also NK) cells likely remain and die in the liver.

Human liver-derived CXCR6+ NK cells are predominantly educated through NKG2A and show reduced cytokine production

“…Initial characterization of hepatic NK cells in our study cohort showed that NK cells were enriched in the liver, predominantly comprising CD56 Bright NK cells with lower CD16 expression. Comparable observations have been made by several other groups indicating that the composition of hepatic NK cells of our study cohort can be considered representative . Assessment of the residency markers CD49a and CXCR6 showed increased frequency in hepatic lymphocytes but also a differential expression between these markers on lymphocytes and NK cells.…”

“…Comparable observations have been made by several other groups indicating that the composition of hepatic NK cells of our study cohort can be considered representative. 23,25,39 Assessment of the residency markers CD49a and CXCR6 showed increased frequency in hepatic lymphocytes but also a differential expression between these markers on lymphocytes and NK cells. CD49a was predominantly expressed by non-NK lymphocytes, whereas NK cells did not express CD49a to a significant degree similar to previous reports.…”

Human NK cells: From development to effector functions

“… 90 , 92 In the human liver, NK cells account for 50% of the total lymphocyte count and comprise hepatic CD56 bright CCR5 + CXCR6 + CD69 + trNKs, transient cNKs, and memory-like NKs. 94 , 95 This high percentage itself shows the extent of their contribution towards detoxification, which is undoubtedly one of the major functions of the liver. Moreover, they promote hepatic tolerance and homeostasis by interacting with hepatocyte HLA-E through the NKG2A inhibitory receptor to prime DCs via the release of TGF-β, eventually resulting in the expansion of CD4 + CD25 + T reg cells.…”

Identification of a distinct NK-like hepatic T-cell population activated by NKG2C in a TCR-independent manner

“…5,7 In particular, the hepatic T-cell population includes more activated and terminally differentiated cells than the PB T-cell population. [8][9][10] In addition, compared to the PB, the liver population is enriched with CD8 + T cells expressing receptors that are typically expressed by NK cells. 11,12 For example, CD8 + T cells expressing killer immunoglobulin-like receptors (KIRs) or NKG2A are more prevalent in the liver than the PB.…”