Abstract
IL-33, a member of the IL-1 family of cytokines, was originally described in 2005 as a promoter of type 2 immune responses. However, recent evidence reveals a more complex picture. This cytokine is released locally as an alarmin upon cellular damage where innate cell types respond to IL-33 by modulating their differentiation and influencing the polarizing signals they provide to T cells at the time of antigen presentation. Moreover, the prominent expression of the IL-33 receptor, ST2, on GATA3+ T helper 2 cells (TH2) demonstrated that IL-33 could have a direct impact on T cells. Recent observations reveal that T-bet+ TH1 cells and Foxp3+ regulatory T (TREG) cells can also express the ST2 receptor, either transiently or permanently. As such, IL-33 can have a direct effect on the dynamics of T cell populations. As IL-33 release was shown to play both an inflammatory and a suppressive role, understanding the complex effect of this cytokine on T cell homeostasis is paramount. In this review, we will focus on the factors that modulate ST2 expression on T cells, the effect of IL-33 on helper T cell responses and the role of IL-33 on TREG cell function.
Highlights
Reviewed by: Mariola Stefania Kurowska-Stolarska, University of Glasgow, United Kingdom Miodrag L
T cell function at mucosal sites is intimately linked to the processes of antigen presentation, polarizing cytokine signaling, migration to inflamed sites and the subsequent adaptation to local conditions
IL-33 was shown to play a major role in this process, illustrating the potential for other, less studied, alarmins to play similar roles
Summary
Biochemical dissection of the IL-33/ST2 pathway in mammalian cell lines was performed using data mined through an extensive survey of the literature [40]. The expression of ST2 was dependent on the binding of STAT5 to the intron 7 of il1rl1 [55] which leads to the production of IL-13 and IL-5, but not IL-4, in vitro, suggesting that STAT5-activating signals, such as IL-2, IL-7 or TSLP are required for the upregulation of ST2 in T H2 cells (Figure 1). The effect of IL-33 on the skewing of T cell responses may play a major role in predisposing to virus-induced asthma through the differentiation of pathogenic TH2 cells over anti-viral T cells [98] These experiments provide further evidence that IL33 influences the function of T cells in disease and this effect is highly dependent on the target tissue of infection and type of pathogen. IL-33 modulates important functions in other compartments of the immune system, notably the innate immune response, which was not addressed here but contributes to the overall response against pathogens [107]
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