CD141⁺ myeloid dendritic cells are enriched in healthy human liver

Abstract

Background & aims: Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused by damage, infection or malignancy. Dendritic cells (DCs) are central to these activities, governing the balance between tolerance and immunity. Most of our knowledge about human liver DCs is derived from studies on peritumoral tissue. Little is known about the phenotype and function of DCs, in particular the recently described CD141(+) subset, in healthy human liver and how this profile is altered in liver disease.

Methods: During liver transplantation, healthy donor and diseased explant livers were perfused and hepatic mononuclear cells isolated. Dendritic cell subset frequency and phenotype were characterised in liver perfusates by flow cytometry and the function of CD141(+) DCs was evaluated by mixed lymphocyte reactions (MLRs) and measuring cytokine secretion.

Results: Almost one third of liver CD11c(+) myeloid DCs (mDCs) expressed CD141 compared to <5% of circulating mDCs. Hepatic CD141(+) DCs demonstrated pro-inflammatory function in allogeneic MLRs, inducing T cell production of interferon gamma (IFN-γ) and interleukin (IL)-17. While CD123(+) plasmacytoid DCs (pDCs) and CD1c(+) mDCs were expanded in diseased liver perfusates, CD141(+) DCs were significantly depleted. Despite their depletion, CD141(+) DCs from explant livers produced markedly increased poly(I:C)-induced IFN lambda (IFN-λ) compared with donor DCs.

Conclusions: Accumulation of CD141(+) DCs in healthy liver, which are significantly depleted in liver disease, suggests differential involvement of mDC subsets in liver immunity.

Keywords: ALD; C-type lectin domain family 9 member A; CLEC9A; DCs; HCC; HCV; HMNCs; Hepatitis C virus; IFN-α; IFN-γ; IFN-λ; IL-17; IL-29; ILT; Liver perfusate; MLR; NASH; TLR; Toll-like receptor; UW; University of Wisconsin; alcoholic liver disease; dendritic cells; hepatic mononuclear cells; hepatitis C virus; hepatocellular carcinoma; immunoglobulin-like transcript; interferon alpha; interferon gamma; interferon lambda; interleukin 17; mDCs; mixed lymphocyte reaction; myeloid dendritic cells; non-alcoholic steatohepatitis; pDCs; plasmacytoid dendritic cells; poly(I:C).