Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs

Lüth, Stefan; Huber, Samuel; Schramm, Christoph; Buch, Thorsten; Zander, S.; Stadelmann, Christine; Brück, Wolfgang; Wraith, David C.; Herkel, Johannes; Lohse, Ansgar W.

doi:10.1172/jci32132

Cited by 119 publications

(155 citation statements)

References 44 publications

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“…Previous studies have shown that Tregs play a critical role in liver tolerance (13,22,23); however, in our study, Foxp3 + Treg numbers did not change in HBV-carrier mice, and CD25 + Treg depletion did not influence HBV persistence (Fig. S3).…”

Section: Resultscontrasting

confidence: 71%

“…Furthermore, adoptive transfer of antigen-specific Tr1 cells induced an IL-10-dependent tolerance in the stringent mouse model of islet transplantation (11). The soluble peptide, myelin basic protein (MBP), could induce Ag-specific Tr1 cell generation, which plays a pivotal role in regulating T-cell tolerance that reverses ongoing experimental autoimmune encephalomyelitis disease in a rat model (12), which is consistent with the observation that MBP expression in mouse liver induces antigen-specific Tregs that protect from experimental autoimmune encephalomyelitis (13). Tr1 cells, in particular, are increased in the livers of patients with recurrent hepatitis C virus (HCV) infection after liver transplantation (14) and also mediate oral tolerance to BSA-induced systemic anaphylaxis (15).…”

supporting

confidence: 77%

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Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Yin

Sun

et al. 2013

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

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The liver plays a critical role in inducing systemic immune tolerance, for example, during limiting hypersensitivity to food allergy and in rendering acceptance of allotransplant or even hepatotropic pathogens. We investigated the unknown mechanisms of liver tolerance by using an established hepatitis B virus (HBV)-carrier mouse model, and found that these mice exhibited an antigen-specific tolerance toward peripheral HBsAg vaccination, showing unenlarged draining lymph node (DLN), lower number of germinal centers (GC), and inactivation of GC B cells and follicular T helper (Tfh) cells. Both in vivo and in vitro immune responses toward HBsAg were suppressed by mononuclear cells from HBV-carrier mice, which were CD4 + Foxp3 − type 1 regulatory T (Tr1)-like cells producing IL-10. Using recipient Rag1 −/− mice, hepatic Tr1-like cells from day 7 of HBV-persistent mice acquired the ability to inhibit anti-HBV immunity 3 d earlier than splenic Tr1-like cells, implying that hepatic Tr1-like cells were generated before those in spleen. Kupffer cell depletion or IL-10 deficiency led to impairment of Tr1-like cell generation, along with breaking HBV persistence. The purified EGFP + CD4 + T cells (containing Tr1-like cells) from HBV-carrier mice trafficked in higher numbers to DLN in recipient mice after HBsAg vaccination, and subsequently inactivated both Tfh cells and GC B cells via secreting IL-10, resulting in impaired GC formation and anti-HB antibody production. Thus, our results indicate Tr1-like cells migrate from the liver to the DLN and inhibit peripheral anti-HBV immunity by negatively regulating GC B cells and Tfh cells.peripheral tolerance | unresponsive

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Section: Resultscontrasting

confidence: 71%

supporting

confidence: 77%

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Yin

Sun

et al. 2013

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

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“…For example, increased transgene expression from the AAV-8 vector correlated with a higher frequency of induced transgene productspecific Tregs, supporting the hypothesis that tolerance induction is facilitated by optimal induction of Tregs. While our published data indicated a requirement for Tregs in tolerance induction by hepatic gene transfer, others have shown that these cells may not only be required but sufficient to prevent certain types of immune responses (Cao et al, 2007a;Hoffman and Herzog, 2008;Luth et al, 2008).…”

Section: Optimal Hepatic Gene Transfer Reduces Impact Of Genetic Factmentioning

confidence: 73%

“…Induced Tregs were capable of suppressing cytotoxic T lymphocyte and antibody responses against F.IX, and were required for tolerance induction (Dobrzynski et al, 2006;Cao et al, 2007a). Once tolerance has been established, supplementary gene transfer to other organs or systemic therapeutic protein delivery can be safely applied (Hoffman et al, 2007;Passini et al, 2007;Sun et al, 2007;Luth et al, 2008). Tolerance induction by liver-restricted transgene expression has been documented for several different transgene products and vectors (Herzog, 2005;Brown et al, 2007;Cerullo et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Improved Induction of Immune Tolerance to Factor IX by Hepatic AAV-8 Gene Transfer

et al. 2009

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Gene therapy for hemophilia B has been shown to result in long-term expression and immune tolerance to factor IX (F.IX) after in vivo transduction of hepatocytes with adeno-associated viral (AAV-2) vectors in experimental animals. An optimized protocol was effective in several strains of mice with a factor 9 gene deletion (F9 À=À ). However, immune responses against F.IX were repeatedly observed in C3H=HeJ F9 À=À mice. We sought to establish a gene transfer protocol that results in sustained expression without a requirement for additional manipulation of the immune system. Compared with AAV-2, AAV-8 was more efficient in transgene expression and induction of tolerance to F.IX in three different strains of wild-type mice. At equal vector doses, AAV-8 induced transgene product-specific regulatory CD4 + CD25 + FoxP3 + T cells at significantly higher frequency. Moreover, sustained correction of hemophilia B in C3H=HeJ F9 À=À mice without antibody formation was documented in all animals treated with !4Â10 11 vector genomes (VG)=kg and in 80% of mice treated with 8Â10 10 VG=kg. Therefore, it is possible to develop a gene transfer protocol that reliably induces tolerance to F.IX largely independent of genetic factors. A comparison with other studies suggests that additional parameters besides plateau levels of F.IX expression contributed to the improved success rate of tolerance induction.

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“…By using the rAAV8 system used in clinical studies, we have recently provided proof of principle that overexpressing a single MHC molecule could lead to silencing of a primed, memory alloreactive response, leading to protection of a skin graft from rejection (14). Similar technology is already approved by the European Commission and European Medicines Agency for Glybera (rAAV1) and could potentially be extended for the induction of tolerance in autoimmune pathologic conditions (38).…”

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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Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs

Cited by 119 publications

References 44 publications

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Liver type I regulatory T cells suppress germinal center formation in HBV-tolerant mice

Improved Induction of Immune Tolerance to Factor IX by Hepatic AAV-8 Gene Transfer

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

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