More recently IL was shown to enhance

More recently, IL-33 was shown to enhance the differentiation programs of diverse T-cell subsets including Th1, Th2, and Treg nos inhibitor via the induction of their respective master regulator transcription factors T-bet, GATA-3 and Foxp3, in addition to inducing their specific signal transducer and activator of transcription (STAT) proteins (Peine et al., 2016). Furthermore, IL-33 was reported to amplify the inflammatory effects of differentiated Th1 and Th2 cell cultures in conjunction with IL-18, another IL-1 family member (Blom and Poulsen, 2012, Samarani et al., 2016). In contrast to its constitutive expression on ILC2, Treg and Th2 cells, ST2 expression on Th1 cells is transient and contributes to virus-specific CD4 T-cell expansion, Th1 effector differentiation, and antiviral cytokine production (Molofsky et al., 2015a, Schmitz et al., 2005). Baumann et al. have shown that ST2 is induced on Th1 effector cells upon differentiation both in vitro and in vivo following lymphocytic choriomeningitis virus (LCMV) infection (Baumann et al., 2015). In Th1 cells, STAT4 and T-bet cooperate to drive ST2 expression. The absence of ST2 on CD4 T-cells impairs Th1 cell activation during viral infection and results in decreased expansion, impaired effector function, and reduced T-cell–mediated immunopathology. Molofsky et al. recently delineated the dynamic role of the IL-33/ST2 axis during microbial invasion with respect to the loss of epithelial integrity at damaged barrier sites (Molofsky et al., 2015b). Following an acute infection causing tissue injury, IL-33 synergized with other epithelial cytokines and chemokines to induce remodeling and to promote tissue homeostasis and repair. However, during chronic infection, a “conversion phase” occurs during which a massive release of IL-33 overwhelms the local regulation mediated by sST2, leading to an inflammatory response that in turn promotes NK, Th1 and cytotoxic CD8 T-cell responses (Bonilla et al., 2012, Molofsky et al., 2015a, Molofsky et al., 2015b, Cao et al., 2016). Over time, this persistent inflammation during chronic infection induces tissue damage and fibrosis (Li et al., 2014a). The IL-33/ST2 axis has been reported to play a role in an increasing number of conditions associated with either tissue necrosis, as in the case of cardiac insufficiency and atherosclerosis (Miller et al., 2008, Miller, 2011), or with breached barriers as in the case of asthma (Li et al., 2014a, Salter et al., 2016), graft vs. host disease (GVHD) (Reichenbach et al., 2015, Vander Lugt et al., 2013), biliary cirrhosis (Volarevic et al., 2012, Sun et al., 2014), ulcerative colitis (UC) and Crohn\'s disease (CD) (Pastorelli et al., 2010). A role for the IL-33/ST2 axis has also been reported in autoimmune diseases such as systemic lupus erythematosus (SLE) (Li et al., 2014b) and rheumatoid arthritis (RA) (Tang et al., 2013), and in different allergic conditions (Cayrol and Girard, 2014, Hayakawa et al., 2007, Nygaard et al., 2016, Salter et al., 2016). Plasma levels of sST2, which are an indirect measure of IL-33 activity, have been used to predict disease outcome and/or to monitor treatment response in a number of conditions including cardiac insufficiency and colitis (Andersson et al., 2016). More recently, the IL-33/ST2 axis was implicated in septic shock (Alves-Filho et al., 2010), and in infections with Dengue virus (Becerra et al., 2008), Toxoplasma gondii (Jones et al., 2010), and Pseudomonas aeruginosa (Hazlett et al., 2010). The molecular and cellular roles of the IL-33/ST2 axis in animal and in human health and disease have been recently reviewed (Jovanovic et al., 2012, Cayrol and Girard, 2014, Rostan et al., 2015, Peine et al., 2016). Herein, we highlight the dynamic role of the IL-33/ST2 axis in the innate and adaptive immune responses that occur during acute and chronic infections, with a focus on HIV, hepatitis B and C viruses (HBV and HCV) and cytomegalovirus (CMV). We also discuss the IL-33/ST2 axis as a potential therapeutic target.