The adult human liver is enriched with natural killer (NK) cells, accounting for 30-50% of hepatic lymphocytes, which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells have altered expression of the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes). Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying humanliver-resident populations. Hepatic NK cells were isolated from donor liver perfusates and biopsies obtained during orthotopic liver transplantation (N = 28). Hepatic CD56 bright NK cells were Eomes hi T-bet lo , a phenotype virtually absent from peripheral blood. These NK cells express the chemokine receptor CXCR6 (chemokine (C-X-C motif) receptor 6), a marker of tissue residency, which is absent from hepatic CD56 dim and blood NK cells. Compared to blood populations, these hepatic CD56 bright NK cells have increased expression of activatory receptors (NKp44, NKp46, and NKG2D). They show reduced ability to produce IFN-γ but enhanced degranulation in response to challenge with target cells. This functionally distinct population of hepatic NK cells constitutes 20-30% of the total hepatic lymphocyte repertoire and represents a tissue-resident immune cell population adapted to the tolerogenic liver microenvironment. Eur. J. Immunol. 2016Immunol. . 46: 2111Immunol. -2120 less cytokines than the CD56 bright population [1,2]. Studies in knockout mice have identified a number of transcription factors essential for the developmental program of NK cells, such as Nfil3, Id2,, as well as the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes) [6,7]. In the bone marrow (BM), T-bet expression is initially repressed, allowing the development of Eomes + NK-cell precursors, with T-bet expression subsequently increased during the final stages of NKcell maturation [6]. While conventional NK cells circulate in the PB, transiting through several organs, significant NK-cell populations also permanently reside in tissues such as the lung, gut, uterus, and liver and may develop there [8]. Among these tissue-resident NK-cell populations, the role of uterine NK cells in successful pregnancy is well described [9]; however, the functions of other heterogeneous tissue-resident NK-cell populations remain largely unknown. Within these tissue microenvironments, it is evident that the developmental, functional, and phenotypic features of NK-cell subsets are poorly characterized compared to their PB counterparts [10].
Keywords: CD56 bright natural killer (NK) cells Human liver Interferon MicroenvironmentThe adult human liver contains a unique and extensive lymphoid repertoire. There is a predominance of innate lymphoid cells including NK cells, NKT cells, mucosal-associated invariant T cells and γδ T cells in the liver, in addition to the presence of conventional CD4 + and CD8 + lymphocytes of ...
