Migration of lymphocytes into hepatic sinusoids
Authors: Ian N. Crispe
Journal: Journal of Hepatology (2012)

Fig. 1. (A) Receptor–ligand pairs directing cells to the liver. Vascular Adhesion Protein-1 (VAP-1) is an adhesion molecule, prominent on hepatic endothelium, that promotes the liver localization of NK cells, CD8+ T cells and CD4+ T cells of the Th2 subset [1Salmi M. Tohka S. Berg E.L. Butcher E.C. Jalkanen S. Vascular adhesion protein 1 (VAP-1) mediates lymphocyte subtype-specific, selectin-independent recognition of vascular endothelium in human lymph nodes.J Exp Med. 1997; 186: 589-600Crossref PubMed Scopus (94) Google Scholar, 2Bonder C.S. Norman M.U. Swain M.G. Zbytnuik L.D. Yamanouchi J. Santamaria P. et al.Rules of recruitment for Th1 and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and vascular adhesion protein-1.Immunity. 2005; 23: 153-163Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar]. VAP-1 binds to Sialic Acid-binding Immunoglobulin-like Lectin (Siglec) molecules; T cell and NK cell adhesion acts via Siglec-10, while granulocyte adhesion to VAP-1 is mediated by Siglec-9 [3Kivi E. Elima K. Aalto K. Nymalm Y. Auvinen K. Koivunen E. et al.Human Siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate.Blood. 2009; 114: 5385-5392Crossref PubMed Scopus (66) Google Scholar, 4Aalto K. Autio A. Kiss E.A. Elima K. Nymalm Y. Veres T.Z. et al.Siglec-9 is a novel leukocyte ligand for vascular adhesion protein-1 and can be used in PET imaging of inflammation and cancer.Blood. 2011; 118: 3725-3733Crossref PubMed Scopus (84) Google Scholar], as well as the interaction of CD44 with hyaluronan [[5]McDonald B. McAvoy E.F. Lam F. Gill V. de la Motte C. Savani R.C. et al.Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids.J Exp Med. 2008; 205: 915-927Crossref PubMed Scopus (260) Google Scholar]. Integrin-mediated adhesion receptors also play an important role in the localization of lymphocytes to the liver. Vascular Cell Adhesion Molecule-1 (VCAM-1) binds to Very Late Antigen-4 (VLA-4; also known as α4β1-integrin) and this interaction is important in the hepatic localization of activated CD8+ T cells, and Th1-type CD4+ T cells [2Bonder C.S. Norman M.U. Swain M.G. Zbytnuik L.D. Yamanouchi J. Santamaria P. et al.Rules of recruitment for Th1 and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and vascular adhesion protein-1.Immunity. 2005; 23: 153-163Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 6John B. Crispe I.N. Passive and active mechanisms trap activated CD8+ T cells in the liver.J Immunol. 2004; 172: 5222-5229PubMed Google Scholar]. These adhesion molecules are involved in antigen-independent homing to the liver, but when T cells recognize an antigen, Intercellular Adhesion Molecule-1 (ICAM-1) assumes greater significance. This is the case both for naïve, and for already-activated CD8+ T cells [6John B. Crispe I.N. Passive and active mechanisms trap activated CD8+ T cells in the liver.J Immunol. 2004; 172: 5222-5229PubMed Google Scholar, 7Bertolino P. Schrage A. Bowen D.G. Klugewitz K. Ghani S. Eulenburg K. et al.Early intrahepatic antigen-specific retention of naive CD8+ T cells is predominantly ICAM-1/LFA-1 dependent in mice.Hepatology. 2005; 42: 1063-1071Crossref PubMed Scopus (45) Google Scholar]. When the hepatic vasculature is inflamed, additional adhesion molecules are expressed. Of particular interest is Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), which is upregulated by both IL-1β and TNF-α [[8]Ando T. Langley R.R. Wang Y. Jordan P.A. Minagar A. Alexander J.S. et al.Inflammatory cytokines induce MAdCAM-1 in murine hepatic endothelial cells and mediate alpha-4 beta-7 integrin dependent lymphocyte endothelial adhesion in vitro.BMC Physiol. 2007; 7: 10Crossref PubMed Scopus (25) Google Scholar], and engages the α4β7 integrin that is prominently expressed on intestinal lymphocytes. This interaction might account for the hepatic trapping of activated gut-derived T cells in inflammatory bowel diseases [[9]Grant A.J. Lalor P.F. Hubscher S.G. Briskin M. Adams D.H. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).Hepatology. 2001; 33: 1065-1072Crossref PubMed Scopus (222) Google Scholar]. (B) Endothelial interactions and transmigration. VAP-1 is a signaling molecule. Ligation by antibodies results in endothelial activation, with signaling via PI-3 kinase, MAP kinases and NF-kappaB, resulting in the increased expression of a battery of adhesion molecules including ICAM-1, VCAM-1 and l-selectin, and also in the secretion of the chemokine CXCL8, a powerful neutrophil attractant [[10]Lalor P.F. Sun P.J. Weston C.J. Martin-Santos A. Wakelam M.J. Adams D.H. Activation of vascular adhesion protein-1 on liver endothelium results in an NF-kappaB-dependent increase in lymphocyte adhesion.Hepatology. 2007; 45: 465-474Crossref PubMed Scopus (89) Google Scholar]. The fenestrae that penetrate the Liver Sinusoidal Endothelial Cells are sites where ICAM-1 and VAP-1 molecules form clusters together with Stabilin-1 (also known as Common Lymphocytic Endothelial and Vascular Endothelial Receptor-1, CLEVER-1). During the migration of human T-regulatory (CD4+, FoxP3+) T cells across cultures of human liver endothelial cells, VAP-1 and ICAM-1 contribute to the adhesion of the cells while Stabilin-1 is critical for transmigration [[11]Shetty S. Weston C.J. Oo Y.H. Westerlund N. Stamataki Z. Youster J. et al.Common lymphatic endothelial and vascular endothelial receptor-1 mediates the transmigration of regulatory T cells across human hepatic sinusoidal endothelium.J Immunol. 2011; 186: 4147-4155Crossref PubMed Scopus (117) Google Scholar]. The "patrolling" of liver sinusoids by NK-T cells depends on CXCR6, the receptor for CXCL16 [[12]Geissmann F. Cameron T.O. Sidobre S. Manlongat N. Kronenberg M. Briskin M.J. et al.Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids.PLoS Biol. 2005; 3: e113Crossref PubMed Scopus (529) Google Scholar]. (C) Infection triggers cell recruitment cascades. Virus infections of the hepatocytes provide both antigen and innate immune signals, resulting in the recruitment of different cell types in a sequence orchestrated largely by cytokine and chemokines. Thus, murine cytomegalovirus (MCMV) infects hepatocytes and results in type 1 Interferon (IFN-α/β) secretion, which activates Kupffer cells, already abundant locally, to secrete the chemokine CCL3 (MIP-1α). This chemokine brings in NK cells to the infected liver, and they secrete IFN-γ [[13]Salazar-Mather T.P. Lewis C.A. Biron C.A. Type I interferons regulate inflammatory cell trafficking and macrophage inflammatory protein 1alpha delivery to the liver.J Clin Invest. 2002; 110: 321-330Crossref PubMed Scopus (134) Google Scholar]. In response to this IFN-γ, parenchymal cells of the liver secrete the chemokines CXCL9 and CXCL10, which interact with the chemokine receptor CXCR3 on CD8+ T cells, causing their accumulation in the infected liver [[14]Hokeness K.L. Deweerd E.S. Munks M.W. Lewis C.A. Gladue R.P. Salazar-Mather T.P. CXCR3-dependent recruitment of antigen-specific T lymphocytes to the liver during murine cytomegalovirus infection.J Virol. 2007; 81: 1241-1250Crossref PubMed Scopus (77) Google Scholar]. The recruitment of CD8+ T cells expressing CXCR3 can also be initiated by TCR-γδ T cells in response to adenovirus [[15]Ajuebor M.N. Jin Y. Gremillion G.L. Strieter R.M. Chen Q. Adegboyega P.A. GammadeltaT cells initiate acute inflammation and injury in adenovirus-infected liver via cytokine–chemokine cross talk.J Virol. 2008; 82: 9564-9576Crossref PubMed Scopus (34) Google Scholar], although in this case, the TCR-γδ T cells also express CXCR3, and promote their own recruitment. In the case of transgenic mice that express the hepatitis B virus genome in hepatocytes, an inflammatory hepatitis develops in which CD8+ T cells are the prime movers, and Gr-1+ granulocytes essential intermediate in the recruitment of other inflammatory cells [[16]Sitia G. Isogawa M. Kakimi K. Wieland S.F. Chisari F.V. Guidotti L.G. Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lymphocytes.Proc Natl Acad Sci USA. 2002; 99: 13717-13722Crossref PubMed Scopus (98) Google Scholar]. The granulocytes promote cell influx through an unusual mechanism that depends on Matrix Metalloproteinases [[17]Sitia G. Isogawa M. Iannacone M. Campbell I.L. Chisari F.V. Guidotti L.G. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs.J Clin Investig. 2004; 113: 1158-1167PubMed Google Scholar]. Another important player in CD8+ T cell accumulation may be platelets, which act in part via CD40 [18Iannacone M. Sitia G. Isogawa M. Whitmire J.K. Marchese P. Chisari F.V. et al.Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus.Proc Natl Acad Sci USA. 2008; 105: 629-634Crossref PubMed Scopus (107) Google Scholar, 19Iannacone M. Sitia G. Isogawa M. Marchese P. Castro M.G. Lowenstein P.R. et al.Platelets mediate cytotoxic T lymphocyte-induced liver damage.Nat Med. 2005; 11: 1167-1169Crossref PubMed Scopus (283) Google Scholar]. The literature of liver lymphocyte accumulation is extensive, and it was not possible to review all known mechanisms in this limited compass. However, this snapshot reveals considerable complexity. Constitutive adhesion mechanisms equip the liver sinusoids to interact with many populations of lymphocytes, while liver infection or inflammation superimposes additional mechanisms. A first responder cell to local injury may use cytokines and chemokines to call in reinforcements, and different cells may play that sentinel role. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.