IL‐33 promotes innate IFN‐γ production and modulates dendritic cell response in LCMV‐induced hepatitis in mice

Abstract

Recent studies have revealed IL-33 as a key factor in promoting antiviral T-cell responses. However, it is less clear as to how IL-33 regulates innate immunity. In this study, we infected wild-type (WT) and IL-33−/− mice with lymphocytic choriomeningitis virus (LCMV) and demonstrated an essential role of infection-induced IL-33 expression for robust innate IFN-γ production in the liver. We first shown that IL-33 deficiency resulted in a marked reduction in the number of IFN-γ+ γδ T and NK cells, but an increase in that of IL-17+ γδ T cells at 16 hours post-infection. Recombinant IL-33 (rIL-33) treatment could reverse such deficiency via increasing IFN-γ-producing γδ T and NK cells, and inhibiting IL-17+ γδ T cells. We also found that rIL-33-induced type 2 innate lymphoid cells (ILC2) were not involved in T-cell responses and liver injury, since the adoptive transfer of ILC2s neither affected the IFN-γ and TNF-α production in T cells, nor liver transferase levels in LCMV-infected mice. Interestingly, we found that while IL-33 was not required for costimulatory molecule expression, it was critical for DC proliferation and cytokine production. Together, this study highlights an essential role of IL-33 in regulating innate IFN-γ-production and DC function during viral hepatitis.

IL-33 Is a Negative Regulator of Vaccine-Induced Antigen-Specific Cellular Immunity

“…Our data indicate that IL-33 inhibits nanoparticle-driven Ag-specific CD8 + T cell and Th1 responses. A positive role for IL-33 was demonstrated in IFN-g production by CTL [cultured with IL-12 alone or together with IL-33 (12)] and in the context of a viral infection [in which IL-33 deficiency lea to reduced NK-cell IFN-g production during acute viral hepatitis (22)]. IL-33 also promoted IFN-g production from hepatic gd T cells (22).…”

Retinoic Acid Regulates Immune Responses by Promoting IL-22 and Modulating S100 Proteins in Viral Hepatitis

“…Intrahepatic lymphocytes were isolated according to our previous method (26). Briefly, liver tissue was digested with collagenase IV (0.05%, Roche Applied Science, Indianapolis, IN) at 37°C for 30 min.…”

“…Under the appropriate liver microenvironment, these DCs have the unique capability of egress from the infective sites to draining lymphoid organs (24, 25). Since DC migration is a prerequisite for effective T cell priming during viral hepatitis, this process is subject to tight immunoregulatory mechanisms involving multiple intrahepatic players and molecular pathways (2, 26, 27). Recently, RA was reported to enhance both arginase (Arg)-1 and inducible nitric oxide synthase (iNOS) expression in IFN-γ-treated DCs, resulting in a tolerogenic phenotype (28).…”

Overview of the IL‐1 family in innate inflammation and acquired immunity

“…In addition to a role for IL‐33 in the Th2 paradigm, there are also studies revealing a role for IL‐33 in classic Th1 diseases such as inflammatory bowel disease and rheumatoid arthritis . IL‐33 also increases the production of IFN‐γ …”