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

Abstract

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.

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“…IL-33 -/-mice showed reduced infiltration of ST2 + Tregs in the liver and developed more severe immune-mediated hepatitis [48]. Similar results were shown in MCMV-infected ST2 -/-mice where ST2 deficiency aggravated liver pathology due to impaired hepatic accumulation of Tregs [49], indicating immunosuppressive function of ST2 + Tregs in liver disease pathogenesis. In the setting of chronic inflammation, it is conceivable that inflammation-triggered IL-33 and AREG expression leads to constitutively active Tregs with high suppressive function providing the basis of an immunotolerant milieu that allows and supports the development of HCC.…”

“…IL-33/ST2 signaling also ensures Treg function and adaption to the inflammatory environment as demonstrated in intestinal inflammation [47]. Interestingly, IL-33-activated ST2 + Tregs infiltrate the inflamed liver during immune-mediated hepatitis [24,48] and murine cytomegalovirus (MCMV)-induced liver damage [49]. IL-33 -/-mice showed reduced infiltration of ST2 + Tregs in the liver and developed more severe immune-mediated hepatitis [48].…”

‘Repair’ Treg Cells in Tissue Injury

“…These results were recently extended to show that liver Tregs responding to infection-induced injury showed a high expression of ST2, and ST2 + Tregs exhibited elevated expression of CD103, KLRG1, CTLA-4, GITR and PD-1 in mice infected with murine cytomegalovirus [43]. Depending on the infection, liver Tregs produce LAP/TGFβ, GARP and granzyme B [43]. …”

“…In parallel to the increased expression of functional makers, the ratio of Treg to leukocytes in non-fibrotic livers was higher than those in livers with fibrosis, which suggested that intrahepatic Tregs limit fibrosis in HCV-infected livers [19]. These results were recently extended to show that liver Tregs responding to infection-induced injury showed a high expression of ST2, and ST2 + Tregs exhibited elevated expression of CD103, KLRG1, CTLA-4, GITR and PD-1 in mice infected with murine cytomegalovirus [43]. Depending on the infection, liver Tregs produce LAP/TGFβ, GARP and granzyme B [43].…”

“…As mentioned above, liver Tregs constitutively express high levels of ST2, and ST2 + Treg exhibit a high proliferative capacity [43], which has also been observed in lung Tregs [30]. Unlike muscle tissues, IL-33 is mainly produced by endothelial cells in the livers of uninfected mice and is produced by macrophages in infected livers [43].…”