Liver sinusoidal cells collecting MHC-I molecules: You can’t get enough of a good thing
Authors: Antonella Carambia, Johannes Herkel
Journal: Journal of Hepatology (2014)

Transfer of MHC-class-I molecules among liver sinusoidal cells facilitates hepatic immune surveillanceJournal of HepatologyVol. 61Issue 3PreviewIn the liver, antigen-presenting cell populations such as Kupffer cells, liver dendritic cells, and liver sinusoidal endothelial cells (LSECs) participate through cross-presentation to CD8 T cells (CTLs) in hepatic immune-regulation and immune-surveillance. The participation of hepatic stellate cells (HSCs) in immune regulation is controversial. Here we studied HSC's contribution to antiviral CTL immunity. Full-Text PDF The liver is constantly confronted with a variable influx of microbial and nutritional components from the gut. The incoming cargo is mostly harmless, but also has the potential to cause liver damage or infection. Various types of liver-resident antigen-presenting cells guard the hepatic sinusoids and maintain immune tolerance under homoestatic conditions [[1]Thomson A.W. Knolle P.A. Antigen-presenting cell function in the tolerogenic liver environment.Nat Rev Immunol. 2010; 10: 753-766Crossref PubMed Scopus (543) Google Scholar]. However, in the presence of damage or danger, these cells can potently activate the effector responses of T cells and induce inflammation [[2]Jenne C.N. Kubes P. Immune surveillance by the liver.Nat Immunol. 2013; 14: 996-1006Crossref PubMed Scopus (632) Google Scholar]. The role of liver dendritic cells (DCs), Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs) in hepatic immune regulation is well established; however, the contribution of hepatic stellate cells (HSCs) to immune responses in the liver is controversially discussed [3Winau F. Hegasy G. Weiskirchen R. Weber S. Cassan C. Sieling P.A. et al.Ito cells are liver-resident antigen-presenting cells for activating T cell responses.Immunity. 2007; 26: 117-129Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 4Ichikawa S. Mucida D. Tyznik A.J. Kronenberg M. Cheroutre H. Hepatic stellate cells function as regulatory bystanders.J Immunol. 2011; 186: 5549-5555Crossref PubMed Scopus (102) Google Scholar, 5Schildberg F.A. Wojtalla A. Siegmund S.V. Endl E. Diehl L. Abdullah Z. et al.Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism.Hepatology. 2011; 54: 262-272Crossref PubMed Scopus (67) Google Scholar]. In their study in this issue of the Journal of Hepatology, Schölzel et al. investigated the role of HSCs in activating CD8 T cells. CD8 T cells recognize antigen peptides bound to MHC I molecules; these peptides usually are derived by proteasomal degradation and represent endogenous antigens [[6]Rock K.L. Farfán-Arribas D.J. Shen L. Proteases in MHC class I presentation and cross-presentation.J Immunol. 2010; 184: 9-15Crossref PubMed Scopus (81) Google Scholar]. However, some cell types, including DCs, LSECs and KCs, have the ability to load onto their MHC I molecules peptides that were derived from exogenous antigens [[7]Ebrahimkhani M.R. Mohar I. Crispe I.N. Cross-presentation of antigen by diverse subsets of murine liver cells.Hepatology. 2011; 54: 1379-1387Crossref PubMed Scopus (73) Google Scholar]. This so called 'cross-presentation' is a means to induce CD8 T cell responses, e.g., to blood-borne antigens [[8]Schurich A. Böttcher J.P. Burgdorf S. Penzler P. Hegenbarth S. Kern M. et al.Distinct kinetics and dynamics of cross-presentation in liver sinusoidal endothelial cells compared to dendritic cells.Hepatology. 2009; 50: 909-919Crossref PubMed Scopus (63) Google Scholar]. Schölzel et al. analysed whether HSCs are able to cross-present blood-borne antigens to facilitate CD8 T cell activation. By using transgenic mice that express distinct MHC I molecules of the H-2Kb haplotype in HSCs under the control of the GFAP promoter (GFAP-Kb), and using an advanced HSC isolation strategy yielding highly pure HSCs, they found that HSCs completely lack cross-presentation competence. However, surprisingly, these GFAP-Kb mice were nonetheless able to induce specific Kb-restricted CD8 T cell activation to blood-borne antigens. Schölzel et al. explain this observation by intercellular transfer of MHC I molecules from the cell-surface of HSCs to LSECs. This intercellular MHC I molecule transfer seems to be akin to 'trogocytosis' (derived from the greek word "trogo", meaning to nibble or to gnaw), a process through which membrane chunks and, with those, MHC molecules can be exchanged between immune cells at the immunological synapse [[9]Davis D.M. Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response.Nat Rev Immunol. 2007; 7: 238-243Crossref PubMed Scopus (219) Google Scholar]. The physiological relevance of trogocytosis is not entirely clear, but it seems to serve the modulation of immune responses, and can have both, reinforcing or inhibitory effects [9Davis D.M. Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response.Nat Rev Immunol. 2007; 7: 238-243Crossref PubMed Scopus (219) Google Scholar, 10Zhou G. Ding Z.C. Fu J. Levitsky H.I. Presentation of acquired peptide-MHC class II ligands by CD4+ regulatory T cells or helper cells differentially regulates antigen-specific CD4+ T cell response.J Immunol. 2011; 186: 2148-2155Crossref PubMed Scopus (35) Google Scholar, 11Nakayama M. Takeda K. Kawano M. Takai T. Ishii N. Ogasawara K. Natural killer (NK)-dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4+ T cells.Proc Natl Acad Sci U S A. 2011; 108: 18360-18365Crossref PubMed Scopus (72) Google Scholar]. What then is the biological meaning of trogocytosis in the liver? Why do LSECs nibble off MHC molecules from their neighbour cells? Recently, it has been shown that in hepatotropic virus infection LSEC-mediated cross-presentation of viral antigens is important for the induction of an efficient CTL response [[12]Wohlleber D. Kashkar H. Gärtner K. Frings M.K. Odenthal M. Hegenbarth S. et al.TNF-induced target cell killing by CTL activated through cross-presentation.Cell Rep. 2012; 2: 478-487Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]. Schölzel et al. assumed that the transfer of MHC-I molecules from HSCs to LSECs might improve anti-viral immunity, by facilitating cross-presentation of viral antigens even under conditions of virus-induced MHC down-regulation. Indeed, the authors showed that GFAP-Kb mice infected with adenovirus manifested Kb-restricted CTL-mediated hepatitis, although Kb in the liver was expressed only by HSCs. This finding could only be explained by transfer of Kb molecules from HSCs to cross-presenting liver cells, such as LSECs, which then induced CTL activation (Fig. 1). Note that the authors show that exchange of MHC-I molecules can occur also between HSCs and liver DCs or Kupffer cells. As DCs and KCs are cross-presenting cells like LSECs [[7]Ebrahimkhani M.R. Mohar I. Crispe I.N. Cross-presentation of antigen by diverse subsets of murine liver cells.Hepatology. 2011; 54: 1379-1387Crossref PubMed Scopus (73) Google Scholar], it is possible that KCs or DCs might also have acquired H-2Kb molecules from HSCs and contributed to antiviral CTL activation in GFAP-Kb mice. Although this is a sound explanation for the occurrence of trogocytosis in liver infection, the biological relevance of trogocytosis in healthy liver is not immediately obvious. Schölzel et al. find hepatic trogocytosis also in non-infected livers, which are replete with MHC molecules, and there is no virus-induced MHC down-regulation to be compensated. It is yet unclear how hepatic trogocytosis is regulated and whether it is increased in liver infection. Given that hepatic trogocytosis seems to occur permanently, what could its relevance be in the healthy liver? It can be assumed that hepatic trogocytosis is an energy consuming activity that is only being performed because it suits a biological need. One might speculate that hepatic trogocytosis not only safeguards antigen presentation for the induction of liver inflammation, but also for tolerance. As trogocytosis in immune cells can include the exchange of co-stimulatory molecules such as CD80 or CD86 [9Davis D.M. Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response.Nat Rev Immunol. 2007; 7: 238-243Crossref PubMed Scopus (219) Google Scholar, 11Nakayama M. Takeda K. Kawano M. Takai T. Ishii N. Ogasawara K. Natural killer (NK)-dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4+ T cells.Proc Natl Acad Sci U S A. 2011; 108: 18360-18365Crossref PubMed Scopus (72) Google Scholar] or co-inhibitory molecules such as PD-L1 [[13]Gary R. Voelkl S. Palmisano R. Ullrich E. Bosch J.J. Mackensen A. Antigen-specific transfer of functional programmed death ligand 1 from human APCs onto CD8+ T cells via trogocytosis.J Immunol. 2012; 188: 744-752Crossref PubMed Scopus (23) Google Scholar], it is likely that these molecules might also be exchanged in hepatic trogocytosis and mediate activating or inhibitory effects to facilitate T cell activation in liver infection or T cell tolerance in healthy liver. Moreover, it is possible that the exchange of peptide-loaded MHC molecules between various liver cell types could increase the visibility of antigen peptides for circulating T cells. This might be of particular relevance for HSCs, which locate in the perisinusoidal space and thus are somewhat hidden from circulating T cells. The display of HSC-derived MHC molecules by LSECs might enhance T cell responses to HSC-derived peptides loaded onto these MHC molecules. However, there is currently no evidence for that assumption and further investigation is needed to clarify the physiological relevance of hepatic trogocytosis. As trogocytosis is a fast process that seems to occur predominantly in the immunological synapse [[9]Davis D.M. Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response.Nat Rev Immunol. 2007; 7: 238-243Crossref PubMed Scopus (219) Google Scholar], it is also conceivable that such MHC I transfer might occur during the interaction between liver-resident cells and circulating T cells. Such transfer of MHC-I molecules from liver cells to circulating immune cells might not only shape the local immune response, but could even facilitate the transport to remote lymphatic tissues. Supported by grants from the Deutsche Forschungsgemeinschaft (SFB 841). The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.