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Coaxing the liver into preventing autoimmune disease in the brain
Brad E. Hoffman and Roland W. Herzog
Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
Address correspondence to: Roland W. Herzog, Cancer and Genetics Research Center, University of Florida, 1376 Mowry Road, Room 203, Gainesville, Florida 32610, USA. Phone: (352) 273-8113; Fax: (352) 273-8342; E-mail: rherzog@ufl.edu.
Find articles by Hoffman, B. in: JCI | PubMed | Google Scholar
Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
Address correspondence to: Roland W. Herzog, Cancer and Genetics Research Center, University of Florida, 1376 Mowry Road, Room 203, Gainesville, Florida 32610, USA. Phone: (352) 273-8113; Fax: (352) 273-8342; E-mail: rherzog@ufl.edu.
Find articles by Herzog, R. in: JCI | PubMed | Google Scholar
Published September 18, 2008 - More info
J Clin Invest. 2008;118(10):3271–3273. https://doi.org/10.1172/JCI37079.
© 2008 The American Society for Clinical Investigation
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Abstract
Tregs are important mediators of immune tolerance to self antigens, and it has been suggested that Treg inactivation may cause autoimmune disease. Therefore, immunotherapy approaches that aim to restore or expand autoantigen-specific Treg activity might be beneficial for the treatment of autoimmune disease. Here we report that Treg-mediated suppression of autoimmune disease can be achieved in vivo by taking advantage of the ability of the liver to promote immune tolerance. Expression of the neural autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune neuroinflammation in a mouse model of multiple sclerosis. Protection from autoimmunity was mediated by MBP-specific CD4+CD25+Foxp3+ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4+CD25– T cell proliferation after antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4+CD25+Foxp3+ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by TGF-β–dependent peripheral conversion from conventional non-Tregs. Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases.
Authors
Stefan Lüth, Samuel Huber, Christoph Schramm, Thorsten Buch, Stefan Zander, Christine Stadelmann, Wolfgang Brück, David C. Wraith, Johannes Herkel, Ansgar W. Lohse
Immune responses are substantially influenced by the context of the tissue in which they occur. For example, brain and liver have both been characterized as immune-privileged sites. The liver is constantly exposed to food antigens and therefore must control inflammatory responses to exogenous antigens. Furthermore, injection of antigen into the portal vein can induce tolerance, and spontaneous acceptance of liver allograft accompanied by donor-specific T cell tolerance has been documented previously (1). The immune system in the brain parenchyma lacks dendritic cells and therefore the ability to prime T cells. However, T cell activation upon immunization at an ectopic site can cause lymphocyte infiltration and inflammatory responses targeting antigens in the brain (2). For example, immunization against myelin basic protein (MBP) — a protein important in the process of nerve myelination — causes EAE in certain strains of mice, and these animals have been used as a model for human MS.
On the other hand, it is also known that antigen administration to specific organs can induce suppressive immune responses that ultimately promote tolerance. Oral and nasal tolerance are extensively studied scenarios in which antigen introduced to mucosal surfaces at optimal doses causes activation of Tregs such as Tr1 or Th3 cells (3–5). These subsets of CD4+ T cells can suppress immune responses by secretion of the cytokines IL-10 and TGF-β. Similarly, antigen administered to the anterior chamber of the eye, another immune-privileged site, is transported to the spleen via a macrophage-like F4/80+ cell (6). Antigen presentation by this cell type in the lymphoid tissue causes activation of CD4+ and CD8+ Tregs and NKT cells, resulting in immune suppression. These examples illustrate how the immune system has evolved to generate cellular mediators of tolerance, which are exposed to antigens in the context of one organ and are capable of subsequently transferring tolerance to a different organ.
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Tregs induced by hepatic antigen expression prevent neuroinflammatory disease
In this issue of the JCI, Lüth et al. report exciting data that illustrate the far-reaching implications of this hepatic tolerance model (20). The authors demonstrate that expression of MBP in the livers of mice via transgenic and gene transfer approaches prevents the neuroinflammation characteristic of EAE, providing what is believed to be the first evidence that the tolerogenic potential of the liver can abrogate development of autoimmune disease even if the target antigen for the inflammatory T cell response is located in a distant organ, in this instance the brain (Figure 1).
Figure 1Prevention of EAE in mice by hepatic expression of MBP. (A) Immunization with MBP-specific peptide normally causes an inflammatory T cell response in the brain in the EAE mouse model of human MS. (B) In the study by Lüth et al. in this issue of the JCI (20), the authors show that hepatic expression of MBP (normally expressed in the central nervous system), accomplished constitutively in liver-specific MBP transgenic mice (not shown) or transiently after gene transfer to liver cells in vivo, results in induction of MBP-specific CD4+CD25+Foxp3+ Tregs. These MBP-specific CD4+CD25+Foxp3+ Tregs suppressed effector CD4+CD25– T cells and converted conventional CD4+CD25– T cells into CD4+CD25+Foxp3+ Tregs, thereby preventing neuroinflammatory disease. Introduction of antigens to the liver may have potential as a preventative or therapeutic intervention for autoimmune disease.
Mechanistically, the authors showed again that peripheral CD4+CD25+Foxp3+ Tregs mediated tolerance, while the results of experiments in T cell receptor transgenic animals showed no evidence for clonal deletion of MBP-reactive effector T cells, despite some level of expression in the thymus of liver MBP–transgenic mice (20). Importantly, expression of MBP in the skin did not protect against EAE, which indicates that expression of this protein in the hepatic environment is critical. In an elegant set of experiments based on adoptive transfer of Tregs and effector T cells labeled with fluorescent dye, the authors showed that Tregs induced by hepatic expression can turn effector T cells into Tregs by inducing expression of the transcription factor Foxp3. Effector T cells lacking TGF-β receptor II were resistant to this infectious tolerance mechanism, indicating dependence on TGF-β signaling. These findings are reminiscent of TGF-β–dependent suppression of CD8+ T cells by CD4+CD25+Foxp3+ Tregs previously reported by Mempel, von Andrian, and colleagues (21) and further substantiate the importance of this cytokine for in vivo suppression.
The current study by Lüth et al. provides insight into how tolerance is manifested following initial induction of Tregs. Consistent with previously published data (12), hepatic-induced tolerance was found to be robust and not broken by immunization with antigen in complete Freund’s adjuvant. In the EAE model, tolerant mice lacked the striking inflammation as well as T cell and macrophage infiltrate seen in the brains of control animals after immunization with MBP (20). The present study opens the door to the treatment of autoimmune disease by antigen administration to the liver. More work will be required to test whether ongoing disease can be reversed, as opposed to prevented.
The study also raises several interesting questions about the mechanism of Treg generation, including whether antigen presentation in the liver or in a lymphoid tissue induces CD4+CD25+Foxp3+ Tregs and which antigen-presenting cells mediate Treg induction. It should be noted that the liver represents a unique microenvironment with several specialized antigen-presenting cells, such as Kupffer cells (resident macrophages), liver sinusoidal endothelial cells, and hepatic dendritic cells, which have all been implicated in T cell activation and tolerance induction (1, 22, 23). Furthermore, suppressive cytokines such as IL-10 and TGF-β are expressed in the liver and have important roles in regulating antigen uptake and presentation as well as T cell activation. In the present study, suppression of MBP-specific effector T cells by Tregs likely occurred at the level of the draining lymph nodes of the site of immunization and perhaps in the spleen. It would be exciting if this model could be further developed to study potential interactions between ectopically induced Tregs and the immune system of the brain.
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