IL‐12 and IL‐15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

Abstract

IntroductionMurine hepatic NK cells exhibit adaptive features, with liver‐specific adhesion molecules CXCR6 and CD49a acting as surface markers.MethodsWe investigated human liver‐resident CXCR6+ and CD49a+ NK cells using RNA sequencing, flow cytometry, and functional analysis. We further assessed the role of cytokines in generating NK cells with these phenotypes from the peripheral blood.ResultsHepatic CD49a+ NK cells could be induced using cytokines and produce high quantities of IFNγ and TNFα, in contrast to hepatic CXCR6+ NK cells. RNA sequencing of liver‐resident CXCR6+ NK cells confirmed a tolerant immature phenotype with reduced expression of markers associated with maturity and cytotoxicity. Liver‐resident double‐positive CXCR6 + CD49a+ hepatic NK cells are immature but maintain high expression of Th1 cytokines as observed for single‐positive CD49a+ NK cells. We show that stimulation with activating cytokines can readily induce upregulation of both CD49a and CXCR6 on NK cells in the peripheral blood. In particular, IL‐12 and IL‐15 can generate CXCR6 + CD49a+ NK cells in vitro from NK cells isolated from the peripheral blood, with comparable phenotypic and functional features to liver‐resident CD49a+ NK cells, including enhanced IFNγ and NKG2C expression.ConclusionIL‐12 and IL‐15 may be key for generating NK cells with a tissue‐homing phenotype and strong Th1 cytokine profile in the blood, and links peripheral activation of NK cells with tissue‐homing. These findings may have important therapeutic implications for immunotherapy of chronic liver disease.

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

“…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 . In contrast, CXCR6 + NK cells were identified in all donors, ranging from 11 to 78%.…”

“…In fact, increased production of collagen was associated with various liver diseases . Both markers were rarely co‐expressed, further indicating that CXCR6 + and CD49a + NK cells are two separate lineages of liver‐resident NK cells (data not shown) . Nevertheless, it was recently demonstrated that both CXCR6 + and CD49a + expressions can be induced in peripheral blood NK cells by exposure to IL‐12 and IL‐15, therefore allocating a new role for these cytokines in inducing a tissue homing phenotype in NK cells .…”

Immune function of plasmacytoid dendritic cells, natural killer cells, and their crosstalk in HBV infection

“…Stimulation of peripheral blood NK cells with activating cytokines, such as IL‐12 and IL‐15, can generate CXCR6 + CD49a + NK cells with similar phenotypic and functional features to liver‐resident CD49a + NK cells, including increased IFNγ and NKG2C expression. Therefore, IL‐12 and IL‐15 might be pivotal cytokines in generating NK cells with a tissue homing phenotype and strong Th1 cytokine profile . In addition, liver CD56 bright NK cells show enhanced expression levels of the transcription factor Hobit.…”

Hepatocellular carcinoma: Prospects for natural killer cell immunotherapy

“…NK cells account for 30%‐50% of the immune cell infiltrate within the normal liver . NK cells mediate anti‐tumour effector responses by direct cytotoxic effects with granule release, antibody mediated cytotoxic effects via CD16 engagement, secretion of interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα), and, cell‐surface expression of Fas ligand (FasL) and tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) .…”

“…They may be long‐lived and are regulated by the transcription factor EOMES, with liver NK cells having higher levels of EOMES compared to peripheral circulating NK cells . Recent work has also suggested that they may be less responsive to cytokines than their peripheral blood counterparts . Thus targeting these intrahepatic NK cells may be challenging, especially in the context of a cirrhotic liver.…”