The liver’s imprint on CD8+ T cell priming
Authors: Percy A. Knolle
Journal: Journal of Hepatology (2012)

Naïve CD8 T cell activation by liver bone marrow-derived cells leads to a “neglected” IL-2low Bimhigh phenotype, poor CTL function and cell deathJournal of HepatologyVol. 57Issue 4PreviewThe occurrence of primary CD8 T cell activation within the liver, unique among the non-lymphoid organs, is now well accepted. However, the outcome of intrahepatic T cell activation remains controversial. We have previously reported that activation initiated by hepatocytes results in a tolerogenic phenotype characterized by low expression of CD25 and IL-2, poor cytotoxic T lymphocyte (CTL) function, and excessive expression of the pro-apoptotic protein Bim. Full-Text PDF The liver is considered to be an organ with unusual immune functions promoting immune tolerance rather than immunity [1Thomson A.W. Knolle P.A. Antigen-presenting cell function in the tolerogenic liver environment.Nat Rev Immunol. 2010; 10: 753-766Crossref PubMed Scopus (539) Google Scholar, 2Crispe I.N. The liver as a lymphoid organ.Annu Rev Immunol. 2009; 27: 147-163Crossref PubMed Scopus (693) Google Scholar]. This unique immune feature is believed to contribute to spontaneous acceptance of orthotopic liver grafts and may impair the capability of the immune system to clear liver infections by hepatotropic viruses, thereby promoting viral persistence and chronic hepatitis. Key to the understanding of liver immunology are the tolerogenic hepatic microenvironment and the local hepatic antigen presenting cells (APC) that have particular features and contribute to hepatic immune regulation through local priming of CD8+ T cells.Hepatic APC cells comprise truly liver-resident cell populations such as hepatocytes but also bone marrow-derived APC such as Kupffer cells or liver dendritic cells. Antigen presentation by liver-resident hepatocytes to naïve CD8+ T cells can lead to hepatocyte-mediated T cell elimination through a process called suicidal emperipolesis, where naïve T cells entering hepatocytes are degraded [[3]Benseler V. Warren A. Vo M. Holz L.E. Tay S.S. Le Couteur D.G. et al.Hepatocyte entry leads to degradation of autoreactive CD8 T cells.Proc Natl Acad Sci USA. 2011; 108: 16735-16740Crossref PubMed Scopus (111) Google Scholar]. Alternatively, incomplete activation of naïve CD8+ T cells has been shown to lead to over-expression of pro-apoptotic molecules, such as the BH3-only protein Bim, that mediates apoptosis in hepatocyte-primed T cells [[4]Holz L.E. Benseler V. Bowen D.G. Bouillet P. Strasser A. O’Reilly L. et al.Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death.Gastroenterology. 2008; 135: 989-997Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. Bone-marrow derived professional APC, such as dendritic cells, are compromised in their ability to elicit adaptive immunity when they lodge in the liver [5De Creus A. Abe M. Lau A.H. Hackstein H. Raimondi G. Thomson A.W. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin.J Immunol. 2005; 174: 2037-2045Crossref PubMed Scopus (134) Google Scholar, 6Castellaneta A. Sumpter T.L. Chen L. Tokita D. Thomson A.W. NOD2 ligation subverts IFN-alpha production by liver plasmacytoid dendritic cells and inhibits their T cell allostimulatory activity via B7-H1 up-regulation.J Immunol. 2009; 183: 6922-6932Crossref PubMed Scopus (66) Google Scholar, 7Matta B.M. Raimondi G. Rosborough B.R. Sumpter T.L. Thomson A.W. IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells.J Immunol. 2012; 188: 5227-5237Crossref PubMed Scopus (77) Google Scholar]. The T cell-intrinsic mechanisms that determine the lack of T cell immunity after local priming by hepatic antigen-presenting cells, however, have not been exhaustively addressed.The article by Holz et al. in this issue of the Journal of Hepatology [[8]Holz L.E. Benseler V. Vo M. McGuffog C. Van Rooijen N. McCaughan G.W. et al.Naive CD8 T cells activation by liver bone marrow-derived cells leads to a “neglected” IL-2(low) Bim(high) phenotype, poor CTL function and cell death.J Hepatol. 2012; 57: 830-836Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] sheds new light on the important question of how the liver microenvironment changes the ability of bone marrow-derived APC to prime naive CD8 T cells. Using the well-defined experimental system of DES-TCR transgenic T cells, recognizing an endogenous peptide in the context of the MHC class I molecule H-2Kb, Holz et al. demonstrate that in bone marrow chimeric mice hepatic bone marrow-derived APC present antigen in an MHC class I – restricted fashion locally in the liver to circulating naïve CD8 T cells. Whereas naïve T cell priming by antigen-presenting hepatocytes leads to a particular T cell phenotype, characterized by low expression levels of CD25/CD54 and high expression of the pro-apoptotic molecule Bim (CD25lowCD54lowBimhi), T cell priming by professional bone marrow-derived APC in secondary lymphatic tissue leads to a CD25hiCD54hiBimlow phenotype [[9]Bowen D.G. Zen M. Holz L. Davis T. McCaughan G.W. Bertolino P. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity.J Clin Invest. 2004; 114: 701-712Crossref PubMed Scopus (274) Google Scholar]. The high expression levels of the pro-apoptotic molecule Bim in T cells following their priming by antigen-presenting hepatocytes correlates with subsequent T cell death and peripheral tolerance [[4]Holz L.E. Benseler V. Bowen D.G. Bouillet P. Strasser A. O’Reilly L. et al.Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death.Gastroenterology. 2008; 135: 989-997Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. Holz et al. report in this issue of the Journal of Hepatology that naïve CD8+ T cell priming by bone marrow-derived APC in the liver leads to a T cell phenotype (CD25hiCD54hiBimhi) that is distinct from that induced by antigen-presenting hepatocytes or by bone marrow-derived antigen-presenting cells in the lymph node. However, these T cells similarly to hepatocyte-primed T cells show increased Bim-dependent apoptosis [[8]Holz L.E. Benseler V. Vo M. McGuffog C. Van Rooijen N. McCaughan G.W. et al.Naive CD8 T cells activation by liver bone marrow-derived cells leads to a “neglected” IL-2(low) Bim(high) phenotype, poor CTL function and cell death.J Hepatol. 2012; 57: 830-836Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar], which reveals the dominance of the liver as immune regulatory organ over the capability of bone marrow-derived APC to elicit T cell immunity.The molecular mechanisms determining the development of this pro-apoptotic state in liver-primed T cells remain generally unclear. It is possible that increased expression levels of co-inhibitory molecules on hepatic bone marrow-derived APC [6Castellaneta A. Sumpter T.L. Chen L. Tokita D. Thomson A.W. NOD2 ligation subverts IFN-alpha production by liver plasmacytoid dendritic cells and inhibits their T cell allostimulatory activity via B7-H1 up-regulation.J Immunol. 2009; 183: 6922-6932Crossref PubMed Scopus (66) Google Scholar, 7Matta B.M. Raimondi G. Rosborough B.R. Sumpter T.L. Thomson A.W. IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells.J Immunol. 2012; 188: 5227-5237Crossref PubMed Scopus (77) Google Scholar, 10Jung K, Kang M, Park C, Choi YH, Jeon Y, Park SH, et al. The protective role of VSIG4 expressed on kupffer cells during immune-mediated liver injury by inducing tolerance of liver T- and NKT-cells. Hepatology, in press. http://dx.doi.org/10.1002/hep.25906.Google Scholar], which are known to impair delivery of co-stimulatory molecules to T cells, elicit the high expression levels of Bim. However, the expression levels of Bim alone in T cells are not predictive of subsequent T cell death, because also central memory T cells, that survive over long periods of time, have been shown to express high levels of Bim [[11]Kurtulus S. Tripathi P. Moreno-Fernandez M.E. Sholl A. Katz J.D. Grimes H.L. et al.Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim.J Immunol. 2011; 186: 5729-5737Crossref PubMed Scopus (73) Google Scholar]. It has been shown that other factors determine whether liver-primed T cells become sensitive to Bim-dependent apoptosis. Expression of the anti-apoptotic molecule Bcl2 functionally antagonizes Bim and promotes survival. T cells primed by hepatocytes or bone marrow-derived APC in the liver have essentially unchanged Bcl2 expression levels [[8]Holz L.E. Benseler V. Vo M. McGuffog C. Van Rooijen N. McCaughan G.W. et al.Naive CD8 T cells activation by liver bone marrow-derived cells leads to a “neglected” IL-2(low) Bim(high) phenotype, poor CTL function and cell death.J Hepatol. 2012; 57: 830-836Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] that are not sufficient to antagonize the increased levels of Bim. Moreover, it was found that IL-7 signaling regulates the pro-apoptotic activity of Bim in peripheral T cell survival also at the posttranslational level [[12]Li W.Q. Guszczynski T. Hixon J.A. Durum S.K. Interleukin-7 regulates Bim proapoptotic activity in peripheral T-cell survival.Mol Cell Biol. 2010; 30: 590-600Crossref PubMed Scopus (30) Google Scholar]. It is of interest to note that hepatocytes express IL-7 during inflammation and thereby locally influence the quality of local T cell responses in the liver [[13]Sawa Y. Arima Y. Ogura H. Kitabayashi C. Jiang J.J. Fukushima T. et al.Hepatic interleukin-7 expression regulates T cell responses.Immunity. 2009; 30: 447-457Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar]. These findings indicate that local antigen-presentation in the liver does not lead to development of T cell survival and immunity under steady-state non-inflammatory conditions but requires hepatocyte-derived signals that are generated during liver inflammation.Interestingly, high expression levels of Bim were also found in HBV-specific CD8+ T cells in patients suffering from chronic hepatitis B [[14]Lopes A.R. Kellam P. Das A. Dunn C. Kwan A. Turner J. et al.Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection.J Clin Invest. 2008; 118: 1835-1845Crossref PubMed Scopus (172) Google Scholar]. It is suspected that Bim-mediated deletion of virus-specific CD8 T cells contributes to the inability of these patients to control HBV infection. It is not possible, however, to conclude from the study by Holz et al. in this issue of the Journal of Hepatology that elevated levels of Bim in HBV-specific CD8+ T cells resulted from intrahepatic T cell priming by bone marrow-derived APC. Cross-presentation is required for potent anti-viral CD8+ T cell immunity [[15]Kurts C. Robinson B.W. Knolle P.A. Cross-priming in health and disease.Nat Rev Immunol. 2010; 10: 403-414Crossref PubMed Scopus (311) Google Scholar], but the experimental system used by Holz et al. precludes the study of cross-presentation of exogenous antigens on MHC class I molecules. Moreover, elevated levels of Bim were also found in CD8 T cells undergoing peripheral deletion following cross-presentation of auto-antigens from pancreatic islets [[16]Parish I.A. Rao S. Smyth G.K. Juelich T. Denyer G.S. Davey G.M. et al.The molecular signature of CD8+ T cells undergoing deletional tolerance.Blood. 2009; 113: 4575-4585Crossref PubMed Scopus (56) Google Scholar]. Therefore, Bim-dependent T cell death to restrict T cell immunity is not a mechanism that is selectively observed following antigen presentation in the liver.Furthermore, not all APC populations in the liver induce high levels of Bim in T cells upon local priming in the liver. Another liver-resident cell populations, i.e. liver sinusoidal endothelial cells, also prime naïve CD8+ T cells but do not induce clonal T cell deletion [17Limmer A. Ohl J. Kurts C. Ljunggren H.G. Reiss Y. Groettrup M. et al.Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance.Nat Med. 2000; 6: 1348-1354Crossref PubMed Scopus (577) Google Scholar, 18Diehl L. Schurich A. Grochtmann R. Hegenbarth S. Chen L. Knolle P.A. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance.Hepatology. 2008; 47: 296-305Crossref PubMed Scopus (208) Google Scholar] or high levels of Bim in T cells (Böttcher and Knolle, unpublished observation) but still induce a non-responsive state towards further stimulation through the T cell receptor. CD8 T cell survival and functionality is critical for development of efficient immunity. Therefore, more research is required to better understand the cell-intrinsic molecular mechanisms of T cell programming following local liver priming by hepatic APC because these events contribute to the pathogenesis of clinically relevant disease such as rejection of liver transplants and chronic viral infection.Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The liver is considered to be an organ with unusual immune functions promoting immune tolerance rather than immunity [1Thomson A.W. Knolle P.A. Antigen-presenting cell function in the tolerogenic liver environment.Nat Rev Immunol. 2010; 10: 753-766Crossref PubMed Scopus (539) Google Scholar, 2Crispe I.N. The liver as a lymphoid organ.Annu Rev Immunol. 2009; 27: 147-163Crossref PubMed Scopus (693) Google Scholar]. This unique immune feature is believed to contribute to spontaneous acceptance of orthotopic liver grafts and may impair the capability of the immune system to clear liver infections by hepatotropic viruses, thereby promoting viral persistence and chronic hepatitis. Key to the understanding of liver immunology are the tolerogenic hepatic microenvironment and the local hepatic antigen presenting cells (APC) that have particular features and contribute to hepatic immune regulation through local priming of CD8+ T cells. Hepatic APC cells comprise truly liver-resident cell populations such as hepatocytes but also bone marrow-derived APC such as Kupffer cells or liver dendritic cells. Antigen presentation by liver-resident hepatocytes to naïve CD8+ T cells can lead to hepatocyte-mediated T cell elimination through a process called suicidal emperipolesis, where naïve T cells entering hepatocytes are degraded [[3]Benseler V. Warren A. Vo M. Holz L.E. Tay S.S. Le Couteur D.G. et al.Hepatocyte entry leads to degradation of autoreactive CD8 T cells.Proc Natl Acad Sci USA. 2011; 108: 16735-16740Crossref PubMed Scopus (111) Google Scholar]. Alternatively, incomplete activation of naïve CD8+ T cells has been shown to lead to over-expression of pro-apoptotic molecules, such as the BH3-only protein Bim, that mediates apoptosis in hepatocyte-primed T cells [[4]Holz L.E. Benseler V. Bowen D.G. Bouillet P. Strasser A. O’Reilly L. et al.Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death.Gastroenterology. 2008; 135: 989-997Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. Bone-marrow derived professional APC, such as dendritic cells, are compromised in their ability to elicit adaptive immunity when they lodge in the liver [5De Creus A. Abe M. Lau A.H. Hackstein H. Raimondi G. Thomson A.W. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin.J Immunol. 2005; 174: 2037-2045Crossref PubMed Scopus (134) Google Scholar, 6Castellaneta A. Sumpter T.L. Chen L. Tokita D. Thomson A.W. NOD2 ligation subverts IFN-alpha production by liver plasmacytoid dendritic cells and inhibits their T cell allostimulatory activity via B7-H1 up-regulation.J Immunol. 2009; 183: 6922-6932Crossref PubMed Scopus (66) Google Scholar, 7Matta B.M. Raimondi G. Rosborough B.R. Sumpter T.L. Thomson A.W. IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells.J Immunol. 2012; 188: 5227-5237Crossref PubMed Scopus (77) Google Scholar]. The T cell-intrinsic mechanisms that determine the lack of T cell immunity after local priming by hepatic antigen-presenting cells, however, have not been exhaustively addressed. The article by Holz et al. in this issue of the Journal of Hepatology [[8]Holz L.E. Benseler V. Vo M. McGuffog C. Van Rooijen N. McCaughan G.W. et al.Naive CD8 T cells activation by liver bone marrow-derived cells leads to a “neglected” IL-2(low) Bim(high) phenotype, poor CTL function and cell death.J Hepatol. 2012; 57: 830-836Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] sheds new light on the important question of how the liver microenvironment changes the ability of bone marrow-derived APC to prime naive CD8 T cells. Using the well-defined experimental system of DES-TCR transgenic T cells, recognizing an endogenous peptide in the context of the MHC class I molecule H-2Kb, Holz et al. demonstrate that in bone marrow chimeric mice hepatic bone marrow-derived APC present antigen in an MHC class I – restricted fashion locally in the liver to circulating naïve CD8 T cells. Whereas naïve T cell priming by antigen-presenting hepatocytes leads to a particular T cell phenotype, characterized by low expression levels of CD25/CD54 and high expression of the pro-apoptotic molecule Bim (CD25lowCD54lowBimhi), T cell priming by professional bone marrow-derived APC in secondary lymphatic tissue leads to a CD25hiCD54hiBimlow phenotype [[9]Bowen D.G. Zen M. Holz L. Davis T. McCaughan G.W. Bertolino P. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity.J Clin Invest. 2004; 114: 701-712Crossref PubMed Scopus (274) Google Scholar]. The high expression levels of the pro-apoptotic molecule Bim in T cells following their priming by antigen-presenting hepatocytes correlates with subsequent T cell death and peripheral tolerance [[4]Holz L.E. Benseler V. Bowen D.G. Bouillet P. Strasser A. O’Reilly L. et al.Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death.Gastroenterology. 2008; 135: 989-997Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. Holz et al. report in this issue of the Journal of Hepatology that naïve CD8+ T cell priming by bone marrow-derived APC in the liver leads to a T cell phenotype (CD25hiCD54hiBimhi) that is distinct from that induced by antigen-presenting hepatocytes or by bone marrow-derived antigen-presenting cells in the lymph node. However, these T cells similarly to hepatocyte-primed T cells show increased Bim-dependent apoptosis [[8]Holz L.E. Benseler V. Vo M. McGuffog C. Van Rooijen N. McCaughan G.W. et al.Naive CD8 T cells activation by liver bone marrow-derived cells leads to a “neglected” IL-2(low) Bim(high) phenotype, poor CTL function and cell death.J Hepatol. 2012; 57: 830-836Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar], which reveals the dominance of the liver as immune regulatory organ over the capability of bone marrow-derived APC to elicit T cell immunity. The molecular mechanisms determining the development of this pro-apoptotic state in liver-primed T cells remain generally unclear. It is possible that increased expression levels of co-inhibitory molecules on hepatic bone marrow-derived APC [6Castellaneta A. Sumpter T.L. Chen L. Tokita D. Thomson A.W. NOD2 ligation subverts IFN-alpha production by liver plasmacytoid dendritic cells and inhibits their T cell allostimulatory activity via B7-H1 up-regulation.J Immunol. 2009; 183: 6922-6932Crossref PubMed Scopus (66) Google Scholar, 7Matta B.M. Raimondi G. Rosborough B.R. Sumpter T.L. Thomson A.W. IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells.J Immunol. 2012; 188: 5227-5237Crossref PubMed Scopus (77) Google Scholar, 10Jung K, Kang M, Park C, Choi YH, Jeon Y, Park SH, et al. The protective role of VSIG4 expressed on kupffer cells during immune-mediated liver injury by inducing tolerance of liver T- and NKT-cells. Hepatology, in press. http://dx.doi.org/10.1002/hep.25906.Google Scholar], which are known to impair delivery of co-stimulatory molecules to T cells, elicit the high expression levels of Bim. However, the expression levels of Bim alone in T cells are not predictive of subsequent T cell death, because also central memory T cells, that survive over long periods of time, have been shown to express high levels of Bim [[11]Kurtulus S. Tripathi P. Moreno-Fernandez M.E. Sholl A. Katz J.D. Grimes H.L. et al.Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim.J Immunol. 2011; 186: 5729-5737Crossref PubMed Scopus (73) Google Scholar]. It has been shown that other factors determine whether liver-primed T cells become sensitive to Bim-dependent apoptosis. Expression of the anti-apoptotic molecule Bcl2 functionally antagonizes Bim and promotes survival. T cells primed by hepatocytes or bone marrow-derived APC in the liver have essentially unchanged Bcl2 expression levels [[8]Holz L.E. Benseler V. Vo M. McGuffog C. Van Rooijen N. McCaughan G.W. et al.Naive CD8 T cells activation by liver bone marrow-derived cells leads to a “neglected” IL-2(low) Bim(high) phenotype, poor CTL function and cell death.J Hepatol. 2012; 57: 830-836Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar] that are not sufficient to antagonize the increased levels of Bim. Moreover, it was found that IL-7 signaling regulates the pro-apoptotic activity of Bim in peripheral T cell survival also at the posttranslational level [[12]Li W.Q. Guszczynski T. Hixon J.A. Durum S.K. Interleukin-7 regulates Bim proapoptotic activity in peripheral T-cell survival.Mol Cell Biol. 2010; 30: 590-600Crossref PubMed Scopus (30) Google Scholar]. It is of interest to note that hepatocytes express IL-7 during inflammation and thereby locally influence the quality of local T cell responses in the liver [[13]Sawa Y. Arima Y. Ogura H. Kitabayashi C. Jiang J.J. Fukushima T. et al.Hepatic interleukin-7 expression regulates T cell responses.Immunity. 2009; 30: 447-457Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar]. These findings indicate that local antigen-presentation in the liver does not lead to development of T cell survival and immunity under steady-state non-inflammatory conditions but requires hepatocyte-derived signals that are generated during liver inflammation. Interestingly, high expression levels of Bim were also found in HBV-specific CD8+ T cells in patients suffering from chronic hepatitis B [[14]Lopes A.R. Kellam P. Das A. Dunn C. Kwan A. Turner J. et al.Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection.J Clin Invest. 2008; 118: 1835-1845Crossref PubMed Scopus (172) Google Scholar]. It is suspected that Bim-mediated deletion of virus-specific CD8 T cells contributes to the inability of these patients to control HBV infection. It is not possible, however, to conclude from the study by Holz et al. in this issue of the Journal of Hepatology that elevated levels of Bim in HBV-specific CD8+ T cells resulted from intrahepatic T cell priming by bone marrow-derived APC. Cross-presentation is required for potent anti-viral CD8+ T cell immunity [[15]Kurts C. Robinson B.W. Knolle P.A. Cross-priming in health and disease.Nat Rev Immunol. 2010; 10: 403-414Crossref PubMed Scopus (311) Google Scholar], but the experimental system used by Holz et al. precludes the study of cross-presentation of exogenous antigens on MHC class I molecules. Moreover, elevated levels of Bim were also found in CD8 T cells undergoing peripheral deletion following cross-presentation of auto-antigens from pancreatic islets [[16]Parish I.A. Rao S. Smyth G.K. Juelich T. Denyer G.S. Davey G.M. et al.The molecular signature of CD8+ T cells undergoing deletional tolerance.Blood. 2009; 113: 4575-4585Crossref PubMed Scopus (56) Google Scholar]. Therefore, Bim-dependent T cell death to restrict T cell immunity is not a mechanism that is selectively observed following antigen presentation in the liver. Furthermore, not all APC populations in the liver induce high levels of Bim in T cells upon local priming in the liver. Another liver-resident cell populations, i.e. liver sinusoidal endothelial cells, also prime naïve CD8+ T cells but do not induce clonal T cell deletion [17Limmer A. Ohl J. Kurts C. Ljunggren H.G. Reiss Y. Groettrup M. et al.Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance.Nat Med. 2000; 6: 1348-1354Crossref PubMed Scopus (577) Google Scholar, 18Diehl L. Schurich A. Grochtmann R. Hegenbarth S. Chen L. Knolle P.A. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance.Hepatology. 2008; 47: 296-305Crossref PubMed Scopus (208) Google Scholar] or high levels of Bim in T cells (Böttcher and Knolle, unpublished observation) but still induce a non-responsive state towards further stimulation through the T cell receptor. CD8 T cell survival and functionality is critical for development of efficient immunity. Therefore, more research is required to better understand the cell-intrinsic molecular mechanisms of T cell programming following local liver priming by hepatic APC because these events contribute to the pathogenesis of clinically relevant disease such as rejection of liver transplants and chronic viral infection. Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.