Deciphering the highway code for lymphocyte traffic along the gut – liver axis
Authors: Antonella Carambia, Johannes Herkel
Journal: Journal of Hepatology (2014)

Influence of CD8 T cell priming in liver and gut on the enterohepatic circulationJournal of HepatologyVol. 60Issue 6PreviewThe enterohepatic circuit of T cells may be responsible for the development of autoimmune liver disease. We employed transgenic mice to characterize phenotype and migration patterns of CD8 T cells activated in liver and gut. Full-Text PDF The mucosal immune compartment of the gut functions as a barrier for microbes and other extrinsic agents that might potentially harm the host [[1]Trivedi P.J. Adams D.H. Mucosal immunity in liver autoimmunity: a comprehensive review.J Autoimmun. 2013; 46: 97-111Crossref PubMed Scopus (87) Google Scholar]. Due to its anatomical position at the confluence of portal and arterial blood, the liver functions as a second barrier for gut-derived pathogens and microbial products [[2]Jenne C.N. Kubes P. Immune surveillance by the liver.Nat Immunol. 2013; 14: 996-1006Crossref PubMed Scopus (632) Google Scholar]. It is believed that this close functional link between gut and liver could explain associations between inflammatory diseases of gut and liver [[1]Trivedi P.J. Adams D.H. Mucosal immunity in liver autoimmunity: a comprehensive review.J Autoimmun. 2013; 46: 97-111Crossref PubMed Scopus (87) Google Scholar]. The most striking example is primary sclerosing cholangitis (PSC) that is marked by portal liver inflammation and bile duct obstruction; more than 80% of these patients suffer from ulcerative colitis as a comorbidity [[1]Trivedi P.J. Adams D.H. Mucosal immunity in liver autoimmunity: a comprehensive review.J Autoimmun. 2013; 46: 97-111Crossref PubMed Scopus (87) Google Scholar]. One explanation for this pathogenic link could be aberrant homing of mucosal lymphocytes to the liver [[1]Trivedi P.J. Adams D.H. Mucosal immunity in liver autoimmunity: a comprehensive review.J Autoimmun. 2013; 46: 97-111Crossref PubMed Scopus (87) Google Scholar]. Indeed, gut-primed T cells were detected in livers of PSC patients [[3]Eksteen B. Mora J.R. Haughton E.L. Henderson N.C. Lee-Turner L. Villablanca E.J. et al.Gut homing receptors on CD8 T cells are retinoic acid dependent and not maintained by liver dendritic or stellate cells.Gastroenterology. 2009; 137: 320-329Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar] and, in a recent murine study, gut-activated CD8 T cells were found to induce antigen-specific cholangitis [[4]Seidel D. Eickmeier I. Kühl A.A. Hamann A. Loddenkemper C. Schott E. CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice.Hepatology. 2014; 59: 601-611Crossref PubMed Scopus (33) Google Scholar]. Conversely, there is evidence that T cells primed in the liver might influence mucosal immune responses in the gut, as CD4 T cells primed by liver sinusoidal endothelial cells (LSECs) have been shown to acquire a gut-homing phenotype [[5]Neumann K. Kruse N. Szilagyi B. Erben U. Rudolph C. Flach A. et al.Connecting liver and gut: murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid.Hepatology. 2012; 55: 1976-1984Crossref PubMed Scopus (28) Google Scholar]. The pathogenic significance and the rules of the proposed mutual T cell traffic along the gut-liver axis are thus far not clear. The present study by Eickmeier et al. in this issue of the Journal of Hepatology provides a systematic analysis of the distinct migration and activation patterns of CD8 T cells that were either primed in the gut or in the liver. By adoptive transfer of naïve ovalbumin (OVA)-specific OT-I cells to transgenic mice displaying gut- or liver-restricted expression of OVA, they generated gut- or liver-primed CD8 T cells in vivo. The differential migration behaviour of gut- or liver-activated OT-I T cells was then investigated in secondary recipients. Confirming previous reports that priming in the gut-associated lymphoid tissue (GALT) confers gut tropism to lymphocytes [[6]Johansson-Lindbom B. Agace W.W. Generation of gut-homing T cells and their localization to the small intestinal mucosa.Immunol Rev. 2007; 215: 226-242Crossref PubMed Scopus (184) Google Scholar], the authors found that gut-activated CD8 T cells preferentially accumulated in the small intestine, rather than in lymphoid tissues. Moreover, gut-activated OT-I T cells were also found to migrate to the livers of recipient mice, as has been already recently reported by the same group [[4]Seidel D. Eickmeier I. Kühl A.A. Hamann A. Loddenkemper C. Schott E. CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice.Hepatology. 2014; 59: 601-611Crossref PubMed Scopus (33) Google Scholar]. Of note, although cognate antigen-expression in the liver of recipient mice further increased hepatic accumulation of gut-activated CD8 T cells, homing to the liver was observed irrespective of hepatic antigen-presentation. These findings indicate that liver infiltration by gut-primed CD8 T cells seems to occur by way of antigen-independent bystander hepatitis. However, the induction of liver pathology was only observed in mice featuring hepatic OVA-expression [[4]Seidel D. Eickmeier I. Kühl A.A. Hamann A. Loddenkemper C. Schott E. CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice.Hepatology. 2014; 59: 601-611Crossref PubMed Scopus (33) Google Scholar]. Apart from the observed liver tropism of gut-activated CD8 T cells, the present study showed that liver-primed CD8 T cells did not accumulate in the gut, suggesting that liver-activated CD8 T cells are not involved in intestinal immune responses. To further explore the different imprints of gut and liver on activation and migration of CD8 T cells, Eickmeier et al. performed transcriptome analysis of gut- or liver-activated CD8 T cells that were isolated from mesenteric lymph nodes or from the liver after in vivo priming. In line with previous reports that intestinal activation by CD103+ dendritic cells (DCs) confers gut tropism to T cells [[6]Johansson-Lindbom B. Agace W.W. Generation of gut-homing T cells and their localization to the small intestinal mucosa.Immunol Rev. 2007; 215: 226-242Crossref PubMed Scopus (184) Google Scholar], gut-activated, but not liver-activated or naïve OT-I T cells displayed significant co-expression of the gut-homing markers CCR9 and α4β7, explaining the observed exclusion of liver-primed CD8 T cells from the gut. However, in the present study, hepatic antigen expression was mainly confined to hepatocytes and it remains to be seen whether priming by other liver antigen presenting cell types might result in diverse migratory behaviors. Although stellate cells and liver dendritic cells were not able to induce CCR9 and α4β7 expression in CD8 T cells [[3]Eksteen B. Mora J.R. Haughton E.L. Henderson N.C. Lee-Turner L. Villablanca E.J. et al.Gut homing receptors on CD8 T cells are retinoic acid dependent and not maintained by liver dendritic or stellate cells.Gastroenterology. 2009; 137: 320-329Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar], it is conceivable that LSECs might be able to induce such phenotype in CD8 T cells, as this was recently shown for LSEC-primed CD4 T cells [[5]Neumann K. Kruse N. Szilagyi B. Erben U. Rudolph C. Flach A. et al.Connecting liver and gut: murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid.Hepatology. 2012; 55: 1976-1984Crossref PubMed Scopus (28) Google Scholar]. In the present study, gut- or liver-specific priming of CD8 T cells occurred under non-inflammatory conditions, however, it is most likely that an inflammatory context during priming greatly influences the activation status and migration behavior of CD8 T cells. Indeed, proinflammatory cytokines or microbial products greatly increase production of T cell-attracting chemokines and adhesion molecules [[1]Trivedi P.J. Adams D.H. Mucosal immunity in liver autoimmunity: a comprehensive review.J Autoimmun. 2013; 46: 97-111Crossref PubMed Scopus (87) Google Scholar], and promote maturation of antigen-presenting cells [[7]Joffre O. Nolte M.A. Spörri R. Reis e Sousa C. Inflammatory signals in dendritic cell activation and the induction of adaptive immunity.Immunol Rev. 2009; 227: 234-247Crossref PubMed Scopus (428) Google Scholar]. In fact, hepatic upregulation of CCL25 and MAdCAM, the respective binding partners for CCR9 and α4β7, has been observed in inflamed livers of PSC patients [[8]Eksteen B. Miles A.E. Grant A.J. Adams D.H. Lymphocyte homing in the pathogenesis of extra-intestinal manifestations of inflammatory bowel disease.Clin Med. 2004; 4: 173-180Crossref PubMed Scopus (61) Google Scholar]. In contrast, Eickmeier et al. did not observe hepatic expression of CCL25 and MAdCAM here, presumably due to the absence of hepatic inflammation in their model. The question then is how hepatic accumulation of gut-derived CD8 T cells occurred, notwithstanding the absence of CCL25 and MAdCAM? One might speculate that additional chemokine ligands such as CXCR3 ligands or integrins that allow binding to ICAM-1 and VCAM-1 [[9]Lalor P.F. Shields P. Grant A. Adams D.H. Recruitment of lymphocytes to the human liver.Immunol Cell Biol. 2002; 80: 52-64Crossref PubMed Scopus (163) Google Scholar] could be responsible for hepatic transendothelial migration of gut-primed CD8 T cells under non-inflammatory conditions. Nonetheless, further studies are needed to investigate how inflammation at the priming site or in the target organ can influence enterohepatic T cell activation and migration. Confirming their previous findings, Eickmeier et al. found that gut-primed CD8 T cells display an activated phenotype. Liver-primed CD8 T cells, however, showed a distinct phenotype with markers of activated (CD44), naïve (CD62L), and central memory cells (Ly6C). Interestingly, liver-activated T cells also expressed Neuropilin-1 (Nrp-1). Note that a similar Nrp-1+ central-memory like phenotype was recently found to be induced in naïve CD8 T cells by liver sinusoidal endothelial cells (LSECs) [[10]Böttcher J.P. Schanz O. Wohlleber D. Abdullah Z. Debey-Pascher S. Staratschek-Jox A. et al.Liver-primed memory T cells generated under noninflammatory conditions provide anti-infectious immunity.Cell Rep. 2013; 3: 779-795Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. These LSEC-primed memory CD8 T cells can acquire effector function upon antigen-specific re-stimulation in an inflammatory environment [[10]Böttcher J.P. Schanz O. Wohlleber D. Abdullah Z. Debey-Pascher S. Staratschek-Jox A. et al.Liver-primed memory T cells generated under noninflammatory conditions provide anti-infectious immunity.Cell Rep. 2013; 3: 779-795Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. Thus, although intrahepatic priming of CD8 T cells usually results in tolerance [[11]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] or an apoptosis-prone phenotype [[12]Holz L.E. Warren A. Le Couteur D.G. Bowen D.G. Bertolino P. CD8+ T cell tolerance following antigen recognition on hepatocytes.J Autoimmun. 2010; 34: 15-22Crossref PubMed Scopus (27) Google Scholar], it is conceivable that LSEC-primed memory CD8 T cells might re-encounter their cognate antigen in the gut and might thereby contribute to mucosal immunity. The recent finding that LSECs can confer a gut-homing phenotype to CD4 T cells [[4]Seidel D. Eickmeier I. Kühl A.A. Hamann A. Loddenkemper C. Schott E. CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice.Hepatology. 2014; 59: 601-611Crossref PubMed Scopus (33) Google Scholar] seems to support this notion. It remains to be seen, whether autoimmune liver diseases might result from inflammatory reactivation in the gut of long-lived memory cells recognizing antigens present in the liver. Indeed, a study by the Adams group, showing a memory-phenotype of CCR9+ T cells in PSC livers, seems to point in this direction [[13]Eksteen B. Grant A.J. Miles A. Curbishley S.M. Lalor P.F. Hübscher S.G. et al.Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.J Exp Med. 2004; 200: 1511-1517Crossref PubMed Scopus (245) Google Scholar]. In addition to the analysis of enterohepatic CD8 T cell migration, future studies should also address the migration patterns of CD4 T cells. Gut-primed CD4 T cells can induce hepatitis in IL10-deficient mice after Trichinella spiralis infection [[14]Douglas D.B. Beiting D.P. Loftus J.P. Appleton J.A. Bliss S.K. Combinatorial effects of interleukin 10 and interleukin 4 determine the progression of hepatic inflammation following murine enteric parasitic infection.Hepatology. 2010; 51: 2162-2171Crossref PubMed Scopus (17) Google Scholar]. Moreover, liver infiltration with Th17 cells has been found in patients suffering from diverse autoimmune liver diseases [[15]Oo Y.H. Banz V. Kavanagh D. Liaskou E. Withers D.R. Humphreys E. et al.CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver.J Hepatol. 2012; 57: 1044-1051Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar]. Since the gut is a prime site of Th17 induction in response to bacterial stimulation [[16]Nutsch K.M. Hsieh C.S. T cell tolerance and immunity to commensal bacteria.Curr Opin Immunol. 2012; 24: 385-391Crossref PubMed Scopus (72) Google Scholar], it seems likely that gut-derived Th17 cells might contribute to hepatic inflammation. 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.