Hepatic interleuklin 15 (IL-15) expression: implications for local NK/NKT cell homeostasis and development.
Interleukin 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 beta-chain (IL-2/IL-15Rbeta; 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-15Rbeta 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-15Rbeta suggesting a local lymphopoietic role. Eighty per cent of NK and 45.8% of CD56(+) T cells expressed IL-2/IL-15Rbeta, suggesting involvement in local CD56(+) cell activation and expansion. Constitutive expression of IL-15 protein and IL-2/IL-15Rbeta 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.
Golden-Mason
L
L
Education and Research Centre, St Vincent's University Hospital, Dublin, Ireland. lucy.golden@ucd.ie
Kelly
A M
AM
Doherty
D G
DG
Traynor
O
O
McEntee
G
G
Kelly
J
J
Hegarty
J E
JE
O'Farrelly
C
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D019409:Interleukin-15 / Q000032:analysis*; D007376:Interleukin-2 / Q000032:analysis; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D019409:Interleukin-15; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2