Hepatitis resulting from liver-specific expression and recognition of self-antigen

Buxbaum, James; Qian, Peiqing; Allen, Paul M.; Peters, Marion G.

doi:10.1016/j.jaut.2008.04.015

Cited by 27 publications

(27 citation statements)

References 24 publications

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“…Regardless of de novo (rAAV.K b treatment in this study) or transgenic [Alb-K b mice (8,13,17,25)] expression, Des T cells activated by hepatocytes never developed into CTL, a finding similarly observed for OT-I T cells activated intrahepatically by de novo-expressed loweraffinity ligands. Overall, a wide variety of outcomes have been reported after intrahepatic CD8 T-cell activation in mice expressing transgenic liver antigens, including ignorance (33), deletional tolerance (8,13,17,25), and partial or full effector differentiation (11,12,24,34). These variable outcomes are likely caused by the different TCR:pMHC affinity and/or levels of antigen expression in these models.…”

Section: Discussionmentioning

confidence: 99%

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

Tay

Wong

McDonald

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

115

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CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adenoassociated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions. rAAV | CTL | TCR | cytotoxicity T he liver is acknowledged to possess unique tolerogenic properties, which have likely evolved to maintain immunological unresponsiveness toward food-derived and microbial antigens that enter the circulation via the gut (1, 2). This tolerogenic capability of the liver is demonstrated in animal models of liver transplantation, in which liver allografts are accepted across complete MHC mismatch barriers and are able to protect other donor tissues from rejection (reviewed in ref.3). In humans, the tolerogenic hepatic environment is likely to contribute to impaired immune clearance of the hepatitis B virus (HBV) and hepatitis C virus (HCV), which result in persistent infection in a significant proportion of exposed individuals and are associated with major morbidity and mortality. In contrast, effective immune responses to hepatotropic pathogens leading to resolution of infection are observed in most hepatitis A and E virus infections, the majority of individuals infected with HBV during adulthood, and a minority of those infected by HCV (reviewed in refs. 4, 5). The liver is also susceptible to a variety of autoimmune-mediated conditions (6). Collectively, these observations indicate that effective immune responses can be initiated and/or sustained in the liver despite its apparent predisposition toward the generation of tolerance. Unfortunately, there is no small animal model in which to study the parameters that determine the balance between intrahepatic immunity and tolerance in viral hepatitis. Thus, the factors that shape immune outcome have not yet been identified.By studying the fate of ...

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Section: Discussionmentioning

confidence: 99%

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

Tay

Wong

McDonald

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

115

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“…Previous studies showed that OT-II and D0.10.11 TCR-Tg CD4 + T cells failed to be activated in mice that expressed OVA by transgenesis or by rAAV-mediated transduction (13,15,16), suggesting that the liver cannot support primary activation of naive CD4 + T cells. To exclude the possibilities that these findings were either due to tolerance to OVA caused by Ag expression from birth or the low-transduction efficacy of type 2 adeno-associated virus (AAV) vectors resulting in a limited amount of Ag available for presentation, we used rAAV vectors pseudotyped to type 8 capsid that were shown to mediate efficient transduction of 100% of hepatocytes in adult mice (17)(18)(19).…”

Section: High Levels Of Ova Expression By Hepatocytes Did Not Lead Tomentioning

confidence: 99%

“…12), but primary CD4 + T cell activation in the liver has never been demonstrated in vivo. In studies in which OVA-specific CD4 + T cells (from TCRtransgenic [Tg] OT-II and D0.10.11 mice) were adoptively transferred into mice expressing OVA in the liver, intrahepatic activation or retention of donor CD4 + T cells was not observed (13)(14)(15)(16). These studies led to the conclusion that naive CD4 + T cells cannot undergo primary activation within the liver, and this was consistent with the paradigm of naive CD4 + T cell homing and activation being restricted to lymphoid organs.…”

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confidence: 99%

“…These studies led to the conclusion that naive CD4 + T cells cannot undergo primary activation within the liver, and this was consistent with the paradigm of naive CD4 + T cell homing and activation being restricted to lymphoid organs. Based on these experiments, it was hypothesized that lack of provision of CD4 help in the liver contributes to failure to develop optimal CD8 + T cell function (13)(14)(15)(16).…”

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confidence: 99%

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Intrahepatic Activation of Naive CD4+ T Cells by Liver-Resident Phagocytic Cells

Tay

Wong

Roediger

et al. 2014

The Journal of Immunology

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Naive T cell activation is normally restricted to the lymphoid organs, in part because of their limited ability to migrate into the parenchyma of peripheral tissues. The liver vasculature is unique, however, and circulating leukocytes within the hepatic sinusoids have direct access to liver-resident cells, which include an abundant population of Kupffer cells. It is well accepted that recognition of cognate Ag within the liver leads to naive CD8+ T cell activation in situ, but it is unclear whether the liver also supports naive CD4+ T cell activation. In this study, we show that naive CD4+ T cells can be activated to proliferate in the liver when cognate Ag expression is induced in hepatocytes by recombinant adeno-associated viral vectors. Ag-specific retention and activation of naive CD4+ T cells within the liver are independent of lymphoid tissues but dependent on a clodronate liposome–sensitive population of liver-resident phagocytic cells. To our knowledge, this study provides the first unequivocal evidence that naive CD4+ T cells can be activated in a nonlymphoid organ. It also gives critical insight into how CD4+ T cells specific for Ag expressed in the liver are recruited to participate in protective or pathological responses during hepatotropic infections and autoimmune liver disease.

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“…In addition to models of PSC, other murine models have been developed to simulate AIH. The intravenous injection of conconavilin A (32) or the injection of antigen-specific T cells into transgenic mice that express novel antigen on the surface of hepatocytes results in the development of T-cell mediated AIH (11). More recently, PBC was shown to develop in IL-2R␣ Ϫ/Ϫ animals.…”

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confidence: 99%

Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease

Brandon¹,

Perez

Jennings³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hepatitis resulting from liver-specific expression and recognition of self-antigen

Cited by 27 publications

References 24 publications

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

Intrahepatic Activation of Naive CD4+ T Cells by Liver-Resident Phagocytic Cells

Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease

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