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Regulatory T cells and autoimmune hepatitis: Defective cells or a hostile environment?
Editorial
Regulatory T cells and autoimmune hepatitis: Defective cells or a hostile environment? Ye H. Oo, David H. Adams⇑ Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK See Article, pages 125–132
Autoimmunity occurs when genetically predisposed individuals are exposed to environmental factors that trigger immune responses to self-antigens. The immune system protects the host by recognising and removing invading pathogens and damaged cells and to do this efficiently it must be able to discriminate between infected or damaged cells and healthy self-tissue. This tolerance of self involves both central, thymic mechanisms and peripheral pathways involving regulatory T cells (Treg) (Fig. 1) [1]. Regulatory T cells are a subpopulation of T cells which downregulate immune responses, maintain tolerance to self-antigens and prevent the development of autoimmunity. CD4 Treg, defined by high levels of CD25, low levels of CD127, and expression of the transcription factor FOXP3, comprise 1–5% of circulating T cells in humans [2]. FOXP3, which regulates their development, is required for suppressive function and mice and human lacking functional FOXP3 develop multiorgan autoimmunity which in humans takes the form of the IPEX syndrome [3]. It is thus logical to look for defective Treg function in autoimmune hepatitis, an archetypal autoimmune disease [4]. Although previous studies reported reduced numbers and defective Treg function in AIH [5–7], Peiseler et al. now report normal frequencies and function of Treg in patients with type 1 AIH; indeed they found higher Treg frequencies in blood and liver tissue during active disease compared with remission. How can these different reports be reconciled? One explanation is the use of better Treg markers in the current study. Earlier studies used CD25 expression to define Treg but CD25 is also expressed on effector CD4 T cells. Peiseler et al. used low levels of CD127 and FOXP3 demethylation to accurately distinguish Treg from effector T cells. In humans, FOXP3 is transiently upregulated during T cell activation but constitutive expression, which is necessary for Treg function, requires demethylation of CpG dinucleotides at the FOXP3 locus providing an epigenetic marker to discriminate between Treg and effector T cells [8]. They also quantified Treg within the liver and confirmed previous findings that intrahepatic Treg frequencies mirror those
DOI of original article: 10.1016/j.jhep.2012.02.029. Corresponding author. E-mail address: [email protected] (D.H. Adams). ⇑
of effector T cells [9]. Thus, on balance, it seems unlikely that a reduced frequency of Treg underlies immune escape in AIH. If Treg are dysfunctional, this could explain failed immune suppression in the presence of normal numbers. Unlike some previous studies, the current paper failed to detect functional defects in Treg during active AIH or during remission. However, a recent study suggests that a combination of reduced Tim-3 levels on effector T cells and Gal9 on Treg renders effector cells resistant to Treg control in AIH [10] implicating defective T cell activation as well as Treg in the failed immune regulation. This draws parallels with studies reporting defective T cell regulation in chronic viral hepatitis [11,12]. Thus, conventional assays of Treg function may be too simplistic to detect specific defects. An additional confounding factor may arise from studying Treg from blood rather than within tissues where they operate. Most published studies show increased hepatic infiltration of Treg in AIH and the relevant cells may have been recruited from the blood into tissue in response to inflammation. The complex cellular and cytokine environment of the inflamed liver may have profound effects on Treg differentiation, stability, and function as well as altering the susceptibility of effector T cells to suppression. In murine models, Treg appear to be functional and stable in the inflamed environment [13] but human hepatic Treg show low levels of phosphorylated STAT-5 consistent with impaired IL-2 receptor signalling [9]. This might be a consequence of reduced secretion or increased consumption of IL-2 within the inflamed liver. Furthermore, Treg in tissue interact with other cells including dendritic and stromal cells which may affect their survival and function and together with local cytokines could reprogramme Treg to express either Tbet and a Th1 phenotype [14] or RORc and a Th-17 phenotype [15]. Thus, understanding the role of Treg in disease depends on better methods to study their interactions and functions within the tissue microenvironment. The normal liver contains specialised antigen-presenting cells, including hepatic dendritic cells and endothelial cells, that promote Treg generation and the presence of TGF-b, IL-10 and retinoic acid further promote the generation and survival of Treg [16]. Such a network may be important to maintain immune homeostasis in the face of gut-derived antigens. This tolerogenic environment is disrupted in hepatitis when the innate immune response to local tissue injury and inflamma-
Journal of Hepatology 2012 vol. 57 j 6–8
JOURNAL OF HEPATOLOGY Environmental factors
Genetics
Hepatic sinusoid Hepatocytes
Endothelial cells
Recruitment via sinusoid CD39 CD4 Kupffer cells
CD25
CXCL9, 10, 11
IFN-γ
Treg Foxp3 Galectin 9 IL-10
IL-10, TGFβ
IFN-γ
Dendritic cells
IL-23R RoRc Th17
Interface/ lobular hepatitis
T-bet Th1
CD8
Recruitment via sinusoid
NKT
Autoantibodies Interface/lobular hepatitis IL-10, TGFβ
IL-1, IL-6 TNF, IFN-γ
NKT
Th17 Th1 Plasma cells
Treg CD8 Bile duct, portal vein, hepatic artery
Hepatocytes
Fig. 1. Regulatory T cell recruitment to the inflamed liver. An initial influx of innate immune cells including NK and NKT leads to the release of IFNc which upregulates CXCR3 ligands and cell adhesion molecules on hepatic sinusoidal endothelium. Consequently, effector T cells and T regulatory cells are recruited via the inflamed hepatic sinusoids and migrate beyond the endothelium to sites of liver inflammation in the portal tracts or hepatic parenchyma. Regulatory T cells are attracted to dendritic cells which modulate their local function and survival. Effector cells cause damage to hepatocytes resulting in interface and lobular hepatitis. Infiltrating T cells, macrophages and stromal cells secrete IFNc, TNFa and other proinflammatory cytokines that result in a microenvironment that promotes the persistence of chronic inflammation. CD4 regulatory T cells can suppress effector cell proliferation and function by secreting immunosuppressive cytokines (IL-10, TGFb) or through contact dependent mechanisms to restore immune homeostasis and promote resolution of hepatitis. The balance of regulatory T cell and effector T cell function will determine whether hepatitis persists or resolves. The fact that Tregs are detected at high frequencies in the liver of patients with AIH suggests that suppression of function locally rather than a basic defect in Treg generation or function underlies the persistence of chronic autoimmune hepatitits.
Journal of Hepatology 2012 vol. 57 j 6–8
7
Editorial tion is followed by the recruitment of effector and regulatory lymphocytes which both use the chemokine receptor CXCR3 to respond to interferon-inducible chemokine ligands at sites of active hepatitis and enter the inflamed liver [17,9,18]. In type 2 AIH, Treg recognise the same autoantigen as effector T cells although the autoantigens in type 1 AIH remain unknown [6]. It is possible that any defects could be confined to the antigen-specific Treg population within the liver and thus not readily detectable by measuring global Treg function in blood. Whether local suppression requires the presence of antigen-specific Treg or can be mediated by non-specific mechanisms remains unknown but is critical for the success of Treg therapy. Another confounding factor is the use of immunosuppressive therapy to treat AIH. In the present study, patients who had untreated active disease had higher frequencies of Treg and effector T cells compared with those with active disease on treatment and those in remission, demonstrating the importance of assessing Treg in untreated patients wherever possible. What are the therapeutic implications of these findings? Clinical trials show efficacy of Treg infusions in clinical GVHD after allogeneic stem cell transplantation [19] and using them to restore immune homeostasis in AIH without the need for toxic immunosuppressive therapy is an attractive option. The finding that functional Treg in AIH are present in blood and liver suggests that therapeutic success will depend on more than simply replacing a defective compartment. There is a need to shift the balance from damage towards resolution of inflammation emphasising the importance of understanding the effects of the local inflammatory microenvironment. Treatment will fail if adoptively transferred Treg are inhibited or pushed into an effector differentiation pathway by local factors in the liver. The use of drugs that maintain Treg differentiation including azacitidine which modulates FOXP3 DNA methylation and the immunosuppressive mTOR inhibitor sirolimus may facilitate Treg stability in vivo [20]. Another important factor is whether therapeutic Treg need to be antigen-specific; if so, such an approach is possible in type 2 AIH where the antigen is known but not in type 1 AIH or other autoimmune liver diseases where the antigen is unknown. Here, one has to hope that polyclonal Treg will be effective. Finally, we need to know how to deliver Treg and whether we want them to exert their action in lymphoid tissue or within the liver itself. Although there are challenges, the recent study showing that IL-2 infusions can mediate immunosuppressive activity associated with increased circulating Treg in HCV-related vasculitis provides encouragement to pursue Treg therapy in autoimmune liver disease [21].
Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
8
References [1] Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133:775–787. [2] Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701–1711. [3] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330–336. [4] Czaja AJ, Manns MP. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis. Gastroenterology 2010;139 (58–72):e54. [5] Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol 2004;41:31–37. [6] Longhi MS, Hussain MJ, Kwok WW, Mieli-Vergani G, Ma Y, Vergani D. Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis. Hepatology 2011;53:536–547. [7] Longhi MS, Hussain MJ, Bogdanos DP, Quaglia A, Mieli-Vergani G, Ma Y, et al. Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2. Hepatology 2007;46:472–484. [8] Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 2007;37:2378–2389. [9] Oo YH, Weston CJ, Lalor PF, Curbishley SM, Withers DR, Reynolds GM, et al. Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol 2010;184:2886–2898. [10] Liberal R, Grant CR, Holder B, Ma Y, Mieli-Vergani G, Vergani D, et al. The impaired immune regulation of autoimmune hepatitis is linked to a defective Galectin-9/Tim-3 pathway. Hepatology 2012. http://dx.doi.org/ 10.1002/hep.25682. [11] Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, et al. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 2009;83:9122–9130. [12] Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P, et al. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005;79:7852–7859. [13] Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, et al. Stability of the regulatory T cell lineage in vivo. Science 2010;329:1667–1671. [14] Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009;10:595–602. [15] Voo KS, Wang YH, Santori FR, Boggiano C, Arima K, Bover L, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 2009;106:4793–4798. [16] Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 2010;10:753–766. [17] Santodomingo-Garzon T, Han J, Le T, Yang Y, Swain MG. Natural killer T cells regulate the homing of chemokine CXC receptor 3-positive regulatory T cells to the liver in mice. Hepatology 2009;49:1267–1276. [18] Curbishley SM, Eksteen B, Gladue RP, Lalor P, Adams DH. CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow. Am J Pathol 2005;167:887–899. [19] Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 2011;117:3921–3928. [20] Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia. Blood 2012;119:3361–3369. [21] Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 2011;365:2067–2077.
Journal of Hepatology 2012 vol. 57 j 6–8
Regulatory T cells and autoimmune hepatitis: Defective cells or a hostile environment? Ye H. Oo, David H. Adams⇑ Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK See Article, pages 125–132
Autoimmunity occurs when genetically predisposed individuals are exposed to environmental factors that trigger immune responses to self-antigens. The immune system protects the host by recognising and removing invading pathogens and damaged cells and to do this efficiently it must be able to discriminate between infected or damaged cells and healthy self-tissue. This tolerance of self involves both central, thymic mechanisms and peripheral pathways involving regulatory T cells (Treg) (Fig. 1) [1]. Regulatory T cells are a subpopulation of T cells which downregulate immune responses, maintain tolerance to self-antigens and prevent the development of autoimmunity. CD4 Treg, defined by high levels of CD25, low levels of CD127, and expression of the transcription factor FOXP3, comprise 1–5% of circulating T cells in humans [2]. FOXP3, which regulates their development, is required for suppressive function and mice and human lacking functional FOXP3 develop multiorgan autoimmunity which in humans takes the form of the IPEX syndrome [3]. It is thus logical to look for defective Treg function in autoimmune hepatitis, an archetypal autoimmune disease [4]. Although previous studies reported reduced numbers and defective Treg function in AIH [5–7], Peiseler et al. now report normal frequencies and function of Treg in patients with type 1 AIH; indeed they found higher Treg frequencies in blood and liver tissue during active disease compared with remission. How can these different reports be reconciled? One explanation is the use of better Treg markers in the current study. Earlier studies used CD25 expression to define Treg but CD25 is also expressed on effector CD4 T cells. Peiseler et al. used low levels of CD127 and FOXP3 demethylation to accurately distinguish Treg from effector T cells. In humans, FOXP3 is transiently upregulated during T cell activation but constitutive expression, which is necessary for Treg function, requires demethylation of CpG dinucleotides at the FOXP3 locus providing an epigenetic marker to discriminate between Treg and effector T cells [8]. They also quantified Treg within the liver and confirmed previous findings that intrahepatic Treg frequencies mirror those
DOI of original article: 10.1016/j.jhep.2012.02.029. Corresponding author. E-mail address: [email protected] (D.H. Adams). ⇑
of effector T cells [9]. Thus, on balance, it seems unlikely that a reduced frequency of Treg underlies immune escape in AIH. If Treg are dysfunctional, this could explain failed immune suppression in the presence of normal numbers. Unlike some previous studies, the current paper failed to detect functional defects in Treg during active AIH or during remission. However, a recent study suggests that a combination of reduced Tim-3 levels on effector T cells and Gal9 on Treg renders effector cells resistant to Treg control in AIH [10] implicating defective T cell activation as well as Treg in the failed immune regulation. This draws parallels with studies reporting defective T cell regulation in chronic viral hepatitis [11,12]. Thus, conventional assays of Treg function may be too simplistic to detect specific defects. An additional confounding factor may arise from studying Treg from blood rather than within tissues where they operate. Most published studies show increased hepatic infiltration of Treg in AIH and the relevant cells may have been recruited from the blood into tissue in response to inflammation. The complex cellular and cytokine environment of the inflamed liver may have profound effects on Treg differentiation, stability, and function as well as altering the susceptibility of effector T cells to suppression. In murine models, Treg appear to be functional and stable in the inflamed environment [13] but human hepatic Treg show low levels of phosphorylated STAT-5 consistent with impaired IL-2 receptor signalling [9]. This might be a consequence of reduced secretion or increased consumption of IL-2 within the inflamed liver. Furthermore, Treg in tissue interact with other cells including dendritic and stromal cells which may affect their survival and function and together with local cytokines could reprogramme Treg to express either Tbet and a Th1 phenotype [14] or RORc and a Th-17 phenotype [15]. Thus, understanding the role of Treg in disease depends on better methods to study their interactions and functions within the tissue microenvironment. The normal liver contains specialised antigen-presenting cells, including hepatic dendritic cells and endothelial cells, that promote Treg generation and the presence of TGF-b, IL-10 and retinoic acid further promote the generation and survival of Treg [16]. Such a network may be important to maintain immune homeostasis in the face of gut-derived antigens. This tolerogenic environment is disrupted in hepatitis when the innate immune response to local tissue injury and inflamma-
Journal of Hepatology 2012 vol. 57 j 6–8
JOURNAL OF HEPATOLOGY Environmental factors
Genetics
Hepatic sinusoid Hepatocytes
Endothelial cells
Recruitment via sinusoid CD39 CD4 Kupffer cells
CD25
CXCL9, 10, 11
IFN-γ
Treg Foxp3 Galectin 9 IL-10
IL-10, TGFβ
IFN-γ
Dendritic cells
IL-23R RoRc Th17
Interface/ lobular hepatitis
T-bet Th1
CD8
Recruitment via sinusoid
NKT
Autoantibodies Interface/lobular hepatitis IL-10, TGFβ
IL-1, IL-6 TNF, IFN-γ
NKT
Th17 Th1 Plasma cells
Treg CD8 Bile duct, portal vein, hepatic artery
Hepatocytes
Fig. 1. Regulatory T cell recruitment to the inflamed liver. An initial influx of innate immune cells including NK and NKT leads to the release of IFNc which upregulates CXCR3 ligands and cell adhesion molecules on hepatic sinusoidal endothelium. Consequently, effector T cells and T regulatory cells are recruited via the inflamed hepatic sinusoids and migrate beyond the endothelium to sites of liver inflammation in the portal tracts or hepatic parenchyma. Regulatory T cells are attracted to dendritic cells which modulate their local function and survival. Effector cells cause damage to hepatocytes resulting in interface and lobular hepatitis. Infiltrating T cells, macrophages and stromal cells secrete IFNc, TNFa and other proinflammatory cytokines that result in a microenvironment that promotes the persistence of chronic inflammation. CD4 regulatory T cells can suppress effector cell proliferation and function by secreting immunosuppressive cytokines (IL-10, TGFb) or through contact dependent mechanisms to restore immune homeostasis and promote resolution of hepatitis. The balance of regulatory T cell and effector T cell function will determine whether hepatitis persists or resolves. The fact that Tregs are detected at high frequencies in the liver of patients with AIH suggests that suppression of function locally rather than a basic defect in Treg generation or function underlies the persistence of chronic autoimmune hepatitits.
Journal of Hepatology 2012 vol. 57 j 6–8
7
Editorial tion is followed by the recruitment of effector and regulatory lymphocytes which both use the chemokine receptor CXCR3 to respond to interferon-inducible chemokine ligands at sites of active hepatitis and enter the inflamed liver [17,9,18]. In type 2 AIH, Treg recognise the same autoantigen as effector T cells although the autoantigens in type 1 AIH remain unknown [6]. It is possible that any defects could be confined to the antigen-specific Treg population within the liver and thus not readily detectable by measuring global Treg function in blood. Whether local suppression requires the presence of antigen-specific Treg or can be mediated by non-specific mechanisms remains unknown but is critical for the success of Treg therapy. Another confounding factor is the use of immunosuppressive therapy to treat AIH. In the present study, patients who had untreated active disease had higher frequencies of Treg and effector T cells compared with those with active disease on treatment and those in remission, demonstrating the importance of assessing Treg in untreated patients wherever possible. What are the therapeutic implications of these findings? Clinical trials show efficacy of Treg infusions in clinical GVHD after allogeneic stem cell transplantation [19] and using them to restore immune homeostasis in AIH without the need for toxic immunosuppressive therapy is an attractive option. The finding that functional Treg in AIH are present in blood and liver suggests that therapeutic success will depend on more than simply replacing a defective compartment. There is a need to shift the balance from damage towards resolution of inflammation emphasising the importance of understanding the effects of the local inflammatory microenvironment. Treatment will fail if adoptively transferred Treg are inhibited or pushed into an effector differentiation pathway by local factors in the liver. The use of drugs that maintain Treg differentiation including azacitidine which modulates FOXP3 DNA methylation and the immunosuppressive mTOR inhibitor sirolimus may facilitate Treg stability in vivo [20]. Another important factor is whether therapeutic Treg need to be antigen-specific; if so, such an approach is possible in type 2 AIH where the antigen is known but not in type 1 AIH or other autoimmune liver diseases where the antigen is unknown. Here, one has to hope that polyclonal Treg will be effective. Finally, we need to know how to deliver Treg and whether we want them to exert their action in lymphoid tissue or within the liver itself. Although there are challenges, the recent study showing that IL-2 infusions can mediate immunosuppressive activity associated with increased circulating Treg in HCV-related vasculitis provides encouragement to pursue Treg therapy in autoimmune liver disease [21].
Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
8
References [1] Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133:775–787. [2] Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701–1711. [3] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330–336. [4] Czaja AJ, Manns MP. Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis. Gastroenterology 2010;139 (58–72):e54. [5] Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol 2004;41:31–37. [6] Longhi MS, Hussain MJ, Kwok WW, Mieli-Vergani G, Ma Y, Vergani D. Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis. Hepatology 2011;53:536–547. [7] Longhi MS, Hussain MJ, Bogdanos DP, Quaglia A, Mieli-Vergani G, Ma Y, et al. Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2. Hepatology 2007;46:472–484. [8] Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 2007;37:2378–2389. [9] Oo YH, Weston CJ, Lalor PF, Curbishley SM, Withers DR, Reynolds GM, et al. Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol 2010;184:2886–2898. [10] Liberal R, Grant CR, Holder B, Ma Y, Mieli-Vergani G, Vergani D, et al. The impaired immune regulation of autoimmune hepatitis is linked to a defective Galectin-9/Tim-3 pathway. Hepatology 2012. http://dx.doi.org/ 10.1002/hep.25682. [11] Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, et al. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 2009;83:9122–9130. [12] Rushbrook SM, Ward SM, Unitt E, Vowler SL, Lucas M, Klenerman P, et al. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005;79:7852–7859. [13] Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, et al. Stability of the regulatory T cell lineage in vivo. Science 2010;329:1667–1671. [14] Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009;10:595–602. [15] Voo KS, Wang YH, Santori FR, Boggiano C, Arima K, Bover L, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 2009;106:4793–4798. [16] Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 2010;10:753–766. [17] Santodomingo-Garzon T, Han J, Le T, Yang Y, Swain MG. Natural killer T cells regulate the homing of chemokine CXC receptor 3-positive regulatory T cells to the liver in mice. Hepatology 2009;49:1267–1276. [18] Curbishley SM, Eksteen B, Gladue RP, Lalor P, Adams DH. CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow. Am J Pathol 2005;167:887–899. [19] Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 2011;117:3921–3928. [20] Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia. Blood 2012;119:3361–3369. [21] Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 2011;365:2067–2077.
Journal of Hepatology 2012 vol. 57 j 6–8