Abstract
The liver is the largest internal organ and filters around 3 pints of blood per minute. This continuous flux of blood should not be confused with rapid egress of lymphocytes through the liver; this organ has intricate corridors of specialized sinusoidal spaces, ensuring that immune cells decelerate to shear flow rates, and providing ample opportunities to interact with parenchymal cells. Migration has been intricately linked to T cell function; it is therefore important to study liver T cell biology into context within the liver microenvironment. Here we discuss the highly organized architecture of liver-resident cells (sinusoidal endothelia, Kupffer cells, stellate cells/myofibroblasts, and biliary and hepatic epithelia) and showcase basic, multicellular, and complex systems to model T cell migration through the human liver microenvironment in vitro and ex vivo.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Masopust D, Schenkel JM (2013) The integration of T cell migration, differentiation and function. Nat Rev Immunol 13:309–320
Horst AK, Neumann K, Diehl L, Tiegs G (2016) Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol 13:277–292
Shetty, S., Weston, C. J., Adams, D. H., and Lalor, P. F. (2014) A flow adhesion assay to study leucocyte recruitment to human hepatic sinusoidal endothelium under conditions of shear stress. J Vis Exp (85):51330
Lalor PF, Herbert J, Bicknell R, Adams DH (2013) Hepatic sinusoidal endothelium avidly binds platelets in an integrin-dependent manner, leading to platelet and endothelial activation and leukocyte recruitment. Am J Physiol Gastrointest Liver Physiol 304:G469–G478
Miles A, Liaskou E, Eksteen B, Lalor PF, Adams DH (2008) CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow. Am J Physiol Gastrointest Liver Physiol 294:G1257–G1267
Alon R, Ley K (2008) Cells on the run: shear-regulated integrin activation in leukocyte rolling and arrest on endothelial cells. Curr Opin Cell Biol 20:525–532
Alon R, Feigelson SW (2009) Chemokine signaling to lymphocyte integrins under shear flow. Microcirculation 16:3–16
Krummel MF, Bartumeus F, Gerard A (2016) T cell migration, search strategies and mechanisms. Nat Rev Immunol 16:193–201
Ju C, Tacke F (2016) Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol 13:316–327
Guidotti LG, Inverso D, Sironi L, Di Lucia P, Fioravanti J, Ganzer L, Fiocchi A, Vacca M, Aiolfi R, Sammicheli S, Mainetti M, Cataudella T, Raimondi A, Gonzalez-Aseguinolaza G, Protzer U, Ruggeri ZM, Chisari FV, Isogawa M, Sitia G, Iannacone M (2015) Immunosurveillance of the liver by intravascular effector CD8(+) T cells. Cell 161:486–500
Warren A, Le Couteur DG, Fraser R, Bowen DG, McCaughan GW, Bertolino P (2006) T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 44:1182–1190
Mrass P, Petravic J, Davenport MP, Weninger W (2010) Cell-autonomous and environmental contributions to the interstitial migration of T cells. Semin Immunopathol 32:257–274
Mazza G, Rombouts K, Rennie Hall A, Urbani L, Vinh Luong T, Al-Akkad W, Longato L, Brown D, Maghsoudlou P, Dhillon AP, Fuller B, Davidson B, Moore K, Dhar D, De Coppi P, Malago M, Pinzani M (2015) Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation. Sci Rep 5:13079
Mazza G, De Coppi P, Gissen P, Pinzani M (2015) Hepatic regenerative medicine. J Hepatol 63:523–524
Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218
Overstreet MG, Gaylo A, Angermann BR, Hughson A, Hyun YM, Lambert K, Acharya M, Billroth-Maclurg AC, Rosenberg AF, Topham DJ, Yagita H, Kim M, Lacy-Hulbert A, Meier-Schellersheim M, Fowell DJ (2013) Inflammation-induced interstitial migration of effector CD4(+) T cells is dependent on integrin alphaV. Nat Immunol 14:949–958
Jacobelli J, Friedman RS, Conti MA, Lennon-Dumenil AM, Piel M, Sorensen CM, Adelstein RS, Krummel MF (2010) Confinement-optimized three-dimensional T cell amoeboid motility is modulated via myosin IIA-regulated adhesions. Nat Immunol 11:953–961
Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R, Hirsch K, Keller M, Forster R, Critchley DR, Fassler R, Sixt M (2008) Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453:51–55
Kim CH (2014) Crawling of effector T cells on extracellular matrix: role of integrins in interstitial migration in inflamed tissues. Cell Mol Immunol 11:1–4
Rennert K, Steinborn S, Groger M, Ungerbock B, Jank AM, Ehgartner J, Nietzsche S, Dinger J, Kiehntopf M, Funke H, Peters FT, Lupp A, Gartner C, Mayr T, Bauer M, Huber O, Mosig AS (2015) A microfluidically perfused three dimensional human liver model. Biomaterials 71:119–131
Jeffery HC, Buckley CD, Moss P, Rainger GE, Nash GB, Mcgettrick HM (2013) Analysis of the effects of stromal cells on the migration of lymphocytes into and through inflamed tissue using 3-D culture models. J Immunol Methods 400-401:45–57
Karim S, Liaskou E, Hadley S, Youster J, Faint J, Adams DH, Lalor PF (2013) An in vitro model of human acute ethanol exposure that incorporates CXCR3- and CXCR4-dependent recruitment of immune cells. Toxicol Sci Off J Soc Toxicol 132:131–141
Lalor PF, Curbishley SM, Adams DH (2010) Identifying homing interactions in T-cell traffic in human disease. Methods Mol Biol 616:231–252
Olinga P, Meijer DK, Slooff MJ, Groothuis GM (1997) Liver slices in in vitro pharmacotoxicology with special reference to the use of human liver tissue. Toxicol In Vitro 12:77–100
Pang KS, Lee WF, Cherry WF, Yuen V, Accaputo J, Fayz S, Schwab AJ, Goresky CA (1988) Effects of perfusate flow rate on measured blood volume, disse space, intracellular water space, and drug extraction in the perfused rat liver preparation: characterization by the multiple indicator dilution technique. J Pharmacokinet Biopharm 16:595–632
Kuse R, Schuster S, Schubbe H, Dix S, Hausmann K (1985) Blood lymphocyte volumes and diameters in patients with chronic lymphocytic leukemia and normal controls. Blut 50:243–248
Acknowledgements
We are grateful to our patient donors, staff, and volunteers at the Queen Elizabeth Hospital NHS Foundation Trust, and staff at the Centre for Liver Research at the University of Birmingham NIHR BRU for Liver Disease for their generous support. This work was supported by a Royal Society Dorothy Hodgkin Fellowship to Z.S. B.W. was funded by a MRC 4-year PhD studentship to Z.S. and K.A. was funded by a Dr. Falk Pharma studentship to GH. This work was supported by facilities funded by the National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media LLC
About this protocol
Cite this protocol
Wiggins, B.G. et al. (2017). In Vitro and Ex Vivo Models to Study T Cell Migration Through the Human Liver Parenchyma. In: Rainger, G., Mcgettrick, H. (eds) T-Cell Trafficking. Methods in Molecular Biology, vol 1591. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6931-9_14
Download citation
DOI: https://doi.org/10.1007/978-1-4939-6931-9_14
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-6929-6
Online ISBN: 978-1-4939-6931-9
eBook Packages: Springer Protocols