Hepatic CD141+IFNλ+ DC subset: One against all?

Abstract

The liver is the key metabolic organ in the human body, which contributes to immune responses against viruses, toxins, bacteria, and parasites. The antigen-rich blood from the gastrointestinal tract flows through a network of liver sinusoids and is scanned by liver antigen-presenting cells [1]. This unique anatomy of the liver may facilitate direct or indirect priming of lymphocytes, modulate the immune response to hepatotropic pathogens and contribute to the immune tolerogenic properties of this organ. The liver specific immune response depends on a specialized intrahepatic cell composition, non-parenchymal cells (NPC), which consists of endothelial cells (liver sinusoidal endothelial cells), Kupffer cells, biliary epithelial cells, hepatic stellate cells, liver associated lymphocytes, and dendritic cells (DCs) [1,2]. DCs develop from bone-marrow progenitor cells, are heterogeneous and consist of several subtypes with a high diversity in phenotype and functional properties [3]. To date five major DC subsets are characterised in lymphoid and non-lymphoid tissue: (i) Langerhans cell (LC), (ii) CD11b-like DCs, (iii) CD8a-like DCs, (iv) plasmacytoid DC (pDC), and (v) monocyte-derived inflammatory-DC [4,5]. The knowledge gained by employing the novel genomic profiling methods revealed that mouse DCs are not representative of human DCs [6] and DCs of both species are different in phenotype and function. For example, the mouse DC surface marker CD8a, which potently cross-present exogenous antigens and which efficiently activate CD8 T cells, is not expressed in human DCs. The study of phenotype and function of human liver DCs is therefore urgently required, not only to understand the pathophysiology of liver disease, but in particular to exploit their therapeutic potential, e.g., for cellular therapy. DCs are lacking the lineage markers and constitutively express MHC class II. In human blood circulation, there are two CD8a-like DC subsets, which could be subdivided by the expression of CD1c (BDCA1) or CD141 (BDCA3) [7]. Recently, CD141 DCs were discovered in human skin, lung, and liver [8]. Moreover, CD141 DCs were detected in the lung of humanized mice that were reconstituted with human hematopoietic progenitors [9]. Studies of non-lymphoid resident DCs in human organs are very restricted due to the availability of the tissues and are limited to