Antigen-Specific Primary Activation of CD8+ T Cells Within the Liver

Bertolino, Patrick; Bowen, David G.; McCaughan, Geoffrey W.; Groth, Barbara Fazekas de St

doi:10.4049/jimmunol.166.9.5430

Cited by 193 publications

(237 citation statements)

References 47 publications

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“…Unfortunately, the induction of immune responses within the liver is known to result in tolerogenic as opposed to immunogenic responses. 4 Therefore, it is unclear where effective immune responses initiate after infection of the liver by exogenous pathogens.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the liver-draining lymph nodes in mice and their role in mounting regional immunity to HBV

Zheng

Tian

2013

Cell Mol Immunol

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The lymphatic system is important in mounting an immune response to foreign antigens and tumors in humans and animal models. The liver produces a large amount of lymph, and its lymphatic system is divided into three major components: the portal, sublobular and superficial lymphatic vessels. Despite the fact that mice are the most commonly used laboratory animals, detailed descriptions of the anatomical location and function of the lymph nodes (LNs) that drain the liver are surprisingly absent. In this study, we found that the portal and celiac LNs adjacent to mouse liver were stained with Evans blue within 5-8 min. Enhanced green fluorescence protein (EGFP)-positive cells from the liver also drained into the two aforementioned LNs. These data indicate that the portal and celiac LNs drain the mouse liver. Lymphadenectomy of the identified liver-draining LNs resulted in hepatitis B virus (HBV) persistence in immunocompetent mice compared with the sham group. In addition, the frequencies of CD81 T cells and dendritic cells (DCs) increased significantly in the liver-draining LNs after hydrodynamic injection of HBV plasmid. Liver-draining LN cells in HBV plasmid-injected mice also showed significant antigen-specific proliferation in response to stimulation with recombinant hepatitis B core antigen in vitro. Adoptive transfer of these cells into Rag1 2/2 mice induced a reduction in the serum concentration of hepatitis B surface antigen (HBsAg) compared to liver-draining LN cells in uninjected mice. Altogether our data characterize the liver-draining LNs and provide evidence that the liver-draining LNs induce an anti-HBV-specific immune response responsible for HBV clearance.

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Section: Introductionmentioning

confidence: 99%

Characterization of the liver-draining lymph nodes in mice and their role in mounting regional immunity to HBV

Zheng

Tian

2013

Cell Mol Immunol

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“…By studying the fate of antigen-specific CD8 T cells transferred into mice expressing antigen in the liver, it has been shown that, despite being a nonlymphoid organ, the liver is able to support primary CD8 T-cell activation (7). However, depending on the choice of antigen expressed and mode of delivery, the outcome of intrahepatic CD8 T-cell activation has been varied, ranging from deletion and/or functional silencing (8)(9)(10) to cytotoxic T lymphocyte (CTL) development (11,12).…”

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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.

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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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“…2,4,5 In addition, hepatocytes, which can upregulate expression of class II molecules of the major histocompatibility complex (MHC II) during hepatitis 6 and may then serve as APC for CD4 ϩ T lymphocytes, 7 also have been implicated in the induction of immune tolerance. 8 Nevertheless, rapid infiltration of the liver with inflammatory cells is induced during infection. However, the mechanisms that mediate the transition from hepatic immune tolerance to hepatic inflammation are not clear.…”

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confidence: 99%

Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells

et al. 2005

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U nder physiological conditions, the liver is basically free of inflammation and the resident antigen-presenting cells (APC) of the liver are believed to actively participate in the maintenance of hepatic immune tolerance. 1 Indeed, the most prevalent professional APC in liver, liver sinusoidal endothelial cells (LSEC) and Kupffer cells (KC), 2,3 have been shown to actively induce immune tolerance. 2,4,5 In addition, hepatocytes, which can upregulate expression of class II molecules of the major histocompatibility complex (MHC II) during hepatitis 6 and may then serve as APC for CD4 ϩ T lymphocytes, 7 also have been implicated in the induction of immune tolerance. 8 Nevertheless, rapid infiltration of the liver with inflammatory cells is induced during infection. However, the mechanisms that mediate the transition from hepatic immune tolerance to hepatic inflammation are not clear.CD4 ϩ CD25 ϩ regulatory T cells (Treg) are important mediators of peripheral immune tolerance: Treg can suppress the activation of autoreactive CD4 ϩ and CD8 ϩ T cells [9][10][11] and also control immune responses during infection. 12,13 Whether Treg are involved in the maintenance of hepatic immune tolerance is not clear; however, recent reports indicate that Treg indeed may suppress hepatic immunity to autoantigen 14 or virus. 15 Thus, it is likely that local suppressive Treg activity needs to be attenuated before liver inflammation can be induced.It has been reported recently that splenic dendritic cells have the capacity to regulate the suppressive activity of Treg 16 : normally, dendritic cells stimulate Treg-mediated suppression; however, in response to microbial stimuli, like lipopolysaccharide (LPS) or immune-stimulatory oli-

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Antigen-Specific Primary Activation of CD8+ T Cells Within the Liver

Cited by 193 publications

References 47 publications

Characterization of the liver-draining lymph nodes in mice and their role in mounting regional immunity to HBV

Characterization of the liver-draining lymph nodes in mice and their role in mounting regional immunity to HBV

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

Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells

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