Pleiotropic Effects of IL-33 on CD4+ T Cell Differentiation and Effector Functions

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 (T_H2) demonstrated that IL-33 could have a direct impact on T cells. Recent observations reveal that T-bet⁺ T_H1 cells and Foxp3⁺ regulatory T (T_REG) 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 T_REG cell function.

Keywords: IL-33; ST2; T cell differentiation; Th17 and Tregs cells; immunoregulation; infection; th1/th2 balance.

Figure 1

Pathways involved in the control of il1rl1 (ST2) transcription in T cells. Summary of the transcription factors confirmed or suggested to interact with the promoter region of il1rl1 (ST2) in T cells. Confirmed (full lines), suggested (dotted lines) and unknown (?) pathways involved in the control of il1rl1 in T cells. (1) IL-33 is required for the maintained expression of ST2 in T cells in T_H2, T_REG, and T_H1 through unknown mechanisms. This process has been suggested to require the involvement of NF-κB translocation and its binding to a consensus sequence in the promoter region of il1rl1. (2) T_H17 cells: The molecular pathways involved in the expression of ST2 in T_H17 T cells remains largely unknown, although the transcription factor STAT3 was shown to bind the promoter region of il1rl1 in fibroblast cell lines. (3) T_H1 cells: Expression of ST2 in T_H1 cells was shown to be dependent on a STAT4 signal leading to T-bet expression, although the molecular interaction with il1rl1 remains unknown. (4) T_H2 cells: It has been suggested that expression of ST2 requires STAT5 signals through the upregulation of GATA3 in conjunction with IL-33 stimulation. Although a STAT6 signal is not necessary, little is known about its role in the maintenance of ST2. (5) T_REG cells: Expression of ST2 on T_REG cells follows a similar pathway as in T_H2 cells, requiring a STAT5 signal and IL-33 activation for the upregulation of GATA3 and ST2. The transcription factors IRF4 and BAFT were also shown to promote expression of ST2 by T_REG cells although little is known about the upstream signals involved.

Figure 2

Effects of IL-33 on T cell functions. IL-33 is a multi-faceted cytokine regulating distinct T cell functions and in a highly context-dependent manner. Known functional outcomes of IL-33 on T cell driven immune responses. (1) T_REG cells: IL-33 increases proliferation of T_REG cells and facilitates the production of amphiregulin, IL-10 and TGFβ as well as low levels of IL-5 and IL-13 in a STAT5-dependent manner. (2) T_H2 cells: IL-33 enhances the proliferation and the expression of IL-5 and IL-13 in T_H2 cells in a STAT5-dependent manner. (3) T_H1 cells: IL-33 was shown to enhance IFNγ production in T_H1 cells in a STAT4-dependent manner. (4) T_H17 cells: IL-33 was shown to inhibit IL-17 production in T_H17 cells. The effects on other T cell functions remains to be assessed.