Hepatic interleuklin 15 (IL-15) expression: implications for local NK/NKT cell homeostasis and development

Abstract

SUMMARYInterleukin 15 (IL-15) is critical for the development of human and murine natural killer (NK) cells and hepatic-derived NK T cells (NKT) in mice, and for the homeostatic maintenance of NK/NKT and CD8 + memory T cells. The lymphocyte repertoire of an adult human liver includes significant populations of NK and NKT-like cells, which may arise locally from hepatic haematopoietic stem cells (HSCs). We investigated hepatic IL-15 levels and the expression of IL-2/IL-15-receptor b -chain (IL-2/IL-15R b ; CD122) on mature hepatic lymphocytes and HSCs. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect secreted/intracellular IL-15 transcripts. IL-15 protein was localized using immunohistochemistry; levels were measured by enzyme-linked immunosorbent assay IL-2/IL-15R b expression by flow-cytometry. Normal hepatic IL-15 protein was detected at 0·43 ng/100 mg total protein ( n = 11, range 0·10 ng -0·9 ng). There was a significant increase in HCV-infected tissue (1·78 ng, P < 0·005, n = 11, range 0·18-2·43 ng). The staining pattern suggests that infiltrating monocytes and tissue resident Kupffer cells are the main producers. IL-15 protein was detected in supernatants from cultured liver biopsy specimens in the absence of stimulation (mean 175·8 pg/100 mg wet tissue, n = 3), which increased significantly upon stimulation ( P < 0·05, mean 231·21 pg). On average, 61% of hepatic HSCs expressed IL-2/IL-15R b suggesting a local lymphopoietic role. Eighty per cent of NK and 45·8% of CD56 + T cells expressed IL-2/IL-15R b , suggesting involvement in local CD56 + cell activation and expansion. Constitutive expression of IL-15 protein and IL-2/IL-15R b on hepatic lymphocytes suggests a key role in the generation and maintenance of the unique hepatic lymphoid repertoire. The significant increase observed in HCV-infected liver suggests a role for IL-15 in host antiviral responses in the liver.

Patient survival by Hsp70 membrane phenotype

“…30,38,39 This may be important in the modulation of the immune response by the liver because Kupffer cells are a rich source of IL-15. 40,41 Thus, the liver can provide an environment for NK cells in which they can selectively eliminate colon and gastric carcinoma cells that express Hsp70 on their surfaces. The better overall survival demonstrated by our Kaplan-Meier analyses may reflect NK cell-mediated killing of tumor cells as they transit the liver.…”

Hepatocytes and IL-15: A Favorable Microenvironment for T Cell Survival and CD8+ T Cell Differentiation

“…The factors responsible for this distinctive intrahepatic population are uncertain, but could include selective recruitment of those lymphocyte subsets from the periphery and/or local generation and differentiation (12,13). Of particular interest is the fact that NKT cells are far more abundant in the liver than in any other place (10,14,15).…”

“…Unlike in mice, human livers contain few CD1d-restricted NKT cells; instead they are enriched for CD3 ϩ CD56 ϩ NKT cells coexpressing an oligoclonal TCR and NKR such as CD94/NKG2 and killer Ig-like receptor (KIR) 4 (16,17), making even more intriguing the origin of this nonclassical NKT cell population. It has been proposed that the unique hepatic microenvironment, through interactions with either epithelial cells or local cytokines, may shape the development of this distinctive intrahepatic population (11,13,18).…”

NK cells: Natural born killers in the conflict between humans and HCV

“…[7][8][9] This finding may be linked to a decrease in serum interleukin (IL)-15, a key cytokine in the development and maintenance of NK homeostasis, 9 although liver expression of IL-15 may be increased. 19 However, even if one focuses on the CD56 dim population it is not clear that there are clear differences in the cytolytic capabilities of these cells when the number of effector cells is taken into account, as the present study and others demonstrate. 7,14 Part of the reason to define the role of different subsets of NK cells is that it is not clear which function of NKcytolysis or production of cytokines such as IFN␥ -may be more relevant in control of HCV.…”