Hepatic CD141+IFNλ+ DC subset: One against all?
Authors: Claudia Wegscheid, Khalil Karimi, Gisa Tiegs
Journal: Journal of Hepatology (2013)

CD141+ myeloid dendritic cells are enriched in healthy human liverJournal of HepatologyVol. 60Issue 1PreviewExtensive 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. Full-Text PDF 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]Racanelli V. Rehermann B. The liver as an immunological organ.Hepatology. 2006; 43: S54-S62Crossref PubMed Scopus (938) Google Scholar]. 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) [1Racanelli V. Rehermann B. The liver as an immunological organ.Hepatology. 2006; 43: S54-S62Crossref PubMed Scopus (938) Google Scholar, 2Thomson A.W. Knolle P.A. Antigen-presenting cell function in the tolerogenic liver environment.Nat Rev Immunol. 2010; 10: 753-766Crossref PubMed Scopus (578) Google Scholar]. DCs develop from bone-marrow progenitor cells, are heterogeneous and consist of several subtypes with a high diversity in phenotype and functional properties [[3]Merad M. Sathe P. Helft J. Miller J. Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting.Annu Rev Immunol. 2013; 31: 563-604Crossref PubMed Scopus (1586) Google Scholar]. 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 [4Heath W.R. Carbone F.R. Dendritic cell subsets in primary and secondary T cell responses at body surfaces.Nat Immunol. 2009; 10: 1237-1244Crossref PubMed Scopus (352) Google Scholar, 5Henri S. Guilliams M. Poulin L.F. Tamoutounour S. Ardouin L. Dalod M. et al.Disentangling the complexity of the skin dendritic cell network.Immunol Cell Biol. 2010; 88: 366-375Crossref PubMed Scopus (85) Google Scholar]. The knowledge gained by employing the novel genomic profiling methods revealed that mouse DCs are not representative of human DCs [[6]Robbins S.H. Walzer T. Dembélé D. Thibault C. Defays A. Bessou G. et al.Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling.Genome Biol. 2008; 9: R17Crossref PubMed Scopus (432) Google Scholar] 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]Dzionek A. Fuchs A. Schmidt P. Cremer S. Zysk M. Miltenyi S. et al.BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood.J Immunol. 2000; 165: 6037-6046Crossref PubMed Scopus (1082) Google Scholar]. Recently, CD141+ DCs were discovered in human skin, lung, and liver [[8]Haniffa M. Shin A. Bigley V. McGovern N. Teo P. See P. et al.Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells.Immunity. 2012; 37: 60-73Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar]. Moreover, CD141+ DCs were detected in the lung of humanized mice that were reconstituted with human hematopoietic progenitors [[9]Poulin L.F. Reyal Y. Uronen-Hansson H. Schraml B.U. Sancho D. Murphy K.M. et al.DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues.Blood. 2012; 119: 6052-6062Crossref PubMed Scopus (195) Google Scholar]. Studies of non-lymphoid resident DCs in human organs are very restricted due to the availability of the tissues and are limited to organs from patients subjected to surgery for an underlying disease. Hence, it is possible that the disease affects the frequency of DCs and their function. So far, there is only the possibility to analyze hepatic DCs phenotype and function from explanted tissues. Acute or chronic liver failure is often associated with pro-inflammatory immune responses. However, for usage of DCs in cellular therapy, studying the steady-state frequency, phenotype, and function of DCs originated from healthy donors are important. Cytokines secreted from DC subsets are critical for modulating immune responses both, in a tolerogenic way by expressing IL-10 or in a pro-inflammatory manner by producing, e.g., TNF-α, IL-6, and IL-1. Additionally, DCs have been reported to secrete IFN-λ in response to viral infection [[10]Donnelly R.P. Kotenko S.V. Interferon-lambda: a new addition to an old family.J Interferon Cytokine Res. 2010; 30: 555-564Crossref PubMed Scopus (334) Google Scholar]. IFN-λ is a type III interferon, which has been reported to be very crucial in the anti-viral immune response towards hepatotropic viruses [[11]Bellanti F. Vendemiale G. Altomare E. Serviddio G. The impact of interferon lambda 3 gene polymorphism on natural course and treatment of hepatitis C.Clin Dev Immunol. 2012; ([http://www.hindawi.com/journals/cdi/2012/849373/abs/])PubMed Google Scholar]. Up to now, human DCs were obtained from digested peritumoral non-lymphoid tissues, e.g., liver and lung [[8]Haniffa M. Shin A. Bigley V. McGovern N. Teo P. See P. et al.Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells.Immunity. 2012; 37: 60-73Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar], where the tumor milieu as well as the isolation method could have affected DC phenotype and function. However, in the current issue of the Journal of Hepatology, Kelly and colleagues describe a very elegant approach to isolate hepatic mononuclear cells (HMNCs) from human healthy adults. Hepatic DCs were isolated during liver transplantation from perfusates of explanted livers of healthy allograft donors without tissue destruction as well as from diseased recipients transplanted for, e.g., hepatocellular carcinoma (HCC) due to HCV infection, HCV infection without HCC, alcoholic liver disease, non-alcoholic steatohepatitis (NASH), and polycystic liver disease. In their study, Kelly and colleagues examined the healthy hepatic DCs in comparison to human blood DCs and the DCs isolated from diseased livers for (i) expression of several surface molecules, (ii) secretion of cytokines in response to poly(I:C) stimulation and (iii) the ability to activate T cells in allogeneic mixed lymphocyte reactions (MLR). Kelly and colleagues demonstrated that the frequencies of resident hepatic DCs are different from those of circulating DCs. Almost half of blood and liver perfusate DC populations are CD11c+ myeloid (m)DCs, however, the ratios of the two CD11c+ subsets, CD1c+ and CD141+, are inverse in blood vs. liver. While the CD1c+ DCs are the main subset in the blood, it is CD141+ DCs, which are the main population within the hepatic DCs. Intrahepatic DCs are predominantly immature cells [[12]Lau A.H. Thomson A.W. Dendritic cells and immune regulation in the liver.Gut. 2003; 52: 307-314Crossref PubMed Scopus (153) Google Scholar]. Under steady state conditions they are tolerogenic and able to inhibit cell proliferation of liver infiltrating lymphocytes. Kelly and colleagues analyzed the CD141+ DC subset for expression of the tolerogenic markers ILT3 and ILT4 [[13]Chang C.C. Ciubotariu R. Manavalan J.S. Yuan J. Colovai A.I. Piazza F. et al.Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4.Nat Immunol. 2002; 3: 237-243Crossref PubMed Scopus (710) Google Scholar] and the C-type lectin receptor CLEC9A that mediates antigen uptake and cross-presentation by human DCs [[14]Schreibelt G. Klinkenberg L.J.J. Cruz L.J. Tacken P.J. Tel J. Kreutz M. et al.The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-) presentation by human blood BDCA3+ myeloid dendritic cells.Blood. 2012; 119: 2284-2292Crossref PubMed Scopus (190) Google Scholar]. Most of hepatic CD11c+ DCs (>90%) are ILT3- and ILT4-positiv. There is only a small CD11c+CD141+CLEC9A+ DC subset (<1%) and of this population roughly 50% of the CD141+ DCs were ILT3+ and ILT4+, probably representing a tolerogenic cell population. The authors also detected a subset of CD141+ DCs with high levels of CLEC9A expression, which are ILT3- and ILT4-negative. These CD141+CLEC9A+ILT3−ILT4− DCs are similar to mouse CD8a+-like DC cells with high capacity for cross presentation [[8]Haniffa M. Shin A. Bigley V. McGovern N. Teo P. See P. et al.Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells.Immunity. 2012; 37: 60-73Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar]. The authors demonstrated that CD141+ DCs activate T cells with a higher proliferation rate in comparison to CD141− DCs and induce an expansion of Th1 and Th17 cells as well as of IFNγ producing CD8+ T cells. Moreover, CD141+ DCs released high amounts of IFN-λ in response to poly(I:C), which mimics viral signals and therefore indicates a possible role for TLR3 mediated immune responses against viral infection by these cells. Interestingly, only a very low frequency of CD141+ DCs was detected in diseased livers, irrespective of the underlying liver disease, however, with an increased potential for IFN-λ production upon poly(I:C) stimulation compared to CD141+ DCs from healthy livers. The method Kelly and colleagues performed to isolate HMNCs from healthy donor livers during orthotopic transplantation seems to be gentle and offers the unique opportunity to characterize DCs and lymphocyte composition of the liver under steady-state conditions. Moreover, DCs could be purified from this population for cellular therapy. During transplantation, University of Wisconsin (UW) solution stored livers were perfused with normal saline. This perfusate as well as the UW solution were used for the cell isolation procedure. There seems to be minimal mechanical stress often observed during crushing of solid tissue as well as a lack of surface molecule disruption by digestive compounds. Therefore, this paper represents a potential major step forward in the study of human liver DCs by highlighting a novel gentle isolation procedure of human DCs, which can be carried out during transplantation surgery without destruction of the transplanted organ and with the opportunity to expand these cells for cellular therapy. However, for a better examination of human hepatic DC subsets, development of in vitro differentiation protocols is necessary. It is important for the development of cellular therapy that the influence of drugs or other compounds can be assayed in these cells in vitro. In the context of cellular immune therapy CD141+CLEC9A+ DCs are a potential cell population that could be employed in clinical applications. Further characterization of this DC subset is necessary to clarify immune regulation of the cells in different pathological circumstances. IFN-λ release by these cells is quite encouraging to use the cells for cellular therapy in chronic viral infection, where boosting of an anti-viral immune response is required. Since the frequency of these cells is greatly reduced in diseased livers, also during viral hepatitis, it would be a reasonable approach to increase the number of the CD141+CLEC9A+ DC subset in the liver, e.g., by adoptive transfer, and thus potentiate cross-presentation of viral antigens to CD8+ T cells, thereby accelerating viral clearance. On the other hand, increase in the frequency of ILT3+ILT4+CD141+ DCs, which are tolerogenic, could be beneficial in the circumstance that the suppression of inflammation is desired (Fig. 1). In conclusion the study presented by Kelly and colleagues gives important information about a new and elegant method to isolate viable cells from human liver tissue. This study also provides very important information about the DC composition in healthy human liver and the changes that occur in DC subsets in diseased liver. The authors who have written this editorial declared that they do not have anything to disclose regarding funding or conflict of interest.