Research Article: IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection

Date Published: April 27, 2017

Publisher: Public Library of Science

Author(s): Branka Popovic, Mijo Golemac, Jürgen Podlech, Jelena Zeleznjak, Lidija Bilic-Zulle, Miodrag L. Lukic, Luka Cicin-Sain, Matthias J. Reddehase, Tim Sparwasser, Astrid Krmpotic, Stipan Jonjic, Chris A. Benedict.


Regulatory T (Treg) cells dampen an exaggerated immune response to viral infections in order to avoid immunopathology. Cytomegaloviruses (CMVs) are herpesviruses usually causing asymptomatic infection in immunocompetent hosts and induce strong cellular immunity which provides protection against CMV disease. It remains unclear how these persistent viruses manage to avoid induction of immunopathology not only during the acute infection but also during life-long persistence and virus reactivation. This may be due to numerous viral immunoevasion strategies used to specifically modulate immune responses but also induction of Treg cells by CMV infection. Here we demonstrate that liver Treg cells are strongly induced in mice infected with murine CMV (MCMV). The depletion of Treg cells results in severe hepatitis and liver damage without alterations in the virus load. Moreover, liver Treg cells show a high expression of ST2, a cellular receptor for tissue alarmin IL-33, which is strongly upregulated in the liver of infected mice. We demonstrated that IL-33 signaling is crucial for Treg cell accumulation after MCMV infection and ST2-deficient mice show a more pronounced liver pathology and higher mortality compared to infected control mice. These results illustrate the importance of IL-33 in the suppressive function of liver Treg cells during CMV infection.

Partial Text

Regulatory CD4+Foxp3+ T (Treg) cells play an essential role in maintaining immune homeostasis and suppressing an overwhelming immune response in several diseased conditions including viral infections and cancer. The transcription factor Foxp3 is essential for Treg cell differentiation and function, thus a mutation in the Foxp3 gene results in an immune-mediated disorder affecting multiple organs in both mice and humans [1]. Beside the naturally occurring Treg cells (nTreg) which mature in the thymus, a variety of induced Treg cells (iTreg) arise from naive CD4+Foxp3− T cells in the periphery, under influence of tissue microenvironment and cytokines [2]. Treg cells employ various immunoregulatory mechanisms including the inhibition of antigen presenting cell function, a direct killing of effector cells, the consumption of IL-2 and the production of immunosuppressive cytokines such as IL-10, TGFβ and IL-35 or amphiregulin [3–5]. However, the phenotype of Treg cells and their suppressive mechanisms differ depending on particular tissue and disease settings [3]. For example, certain subsets of Treg cells, specifically those in adipose tissue and intestines, express high amounts of the IL-33 receptor ST2, and require IL-33 for their maintenance and suppressive function [6]. Tissue alarmin IL-33 has been associated with the differentiation and function of various lymphocytes including Treg cells. In addition to T helper 2 (Th2) cells, Treg cells constitutively express high amounts of ST2, unlike other CD4+ and CD8+ T cell subsets [7].

Treg cells control immune responses under both physiological and pathological conditions. Although the role of Treg cells in homeostasis of immune response and the prevention of immunopathology is well established in different disease models, less is known about their role in the prevention of immunopathology during various viral infections. Many viruses, particularly herpes viruses, encode numerous genes aimed at suppressing the immune response; by doing so they may also prevent immunopathology [38]. CMV is widely spread among mammalian hosts and is usually well controlled by the immune system. However, CMVs establish lifelong persistent (latent) infection from which reactivation can occur whenever the immune response is compromised. Here we show that Treg cells are essential in limiting liver damage during the immune response to primary CMV infection. Liver Treg cells expand 2-3-fold and upregulate their activation markers upon MCMV infection. Ablation of Treg cells in MCMV infected mice led to a significant increase in liver pathology and consequent body weight loss. Liver pathology in Treg depleted mice correlated with an enhanced CD8+ T cell response but not with virus load. Similar to previous studies, no significant difference of virus titers was observed between Treg depleted and non-depleted mice or mice in which Treg cells were selectively expanded to avoid graft-versus-host disease [16, 39]. We have shown that CD8+ T cells readily accumulate in liver of CMV infected mice and are heavily activated, and that a significant proportion of them express granzyme B and IFNγ. It has been well established that the T cell response to viral infections contributes not only to limit viral replication but can also cause immunopathology if the response is not properly regulated [40]. Primary infection with non-cytolytic viruses such as hepatitis C virus (HCV) and hepatitis B virus (HBV), results in T cell mediated immunopathology in the liver [8, 41]. Being a cytolytic virus, CMV is not a prototype of virus that induces immunopathology in the immunocompetent host. Yet, recently evidence has been gathered pointing out that part of liver pathology after MCMV infection is a consequence of the immune response rather than the virus infection itself [42, 43]. The absence of liver pathology in MCMV infected SCID mice suggests the role of T cell immunity in liver damage. Here we confirm these observations and provide evidence that Treg cells dampen an exaggerated immune response and are crucial for the prevention of CMV-induced immunopathology in the liver. This is further supported by our observation of a strong proliferative capacity and activation status of liver Treg cells.




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