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 (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.

SeXX Matters in Multiple Sclerosis

“…A recent investigation provided interesting data regarding sex differences in IL-33 (112), a cytokine that modulates Th2 responses and decreases the differentiation of T cells into highly proinflammatory Th17 cells (195,196). IL-33 expression is increased in NAWM and lesions of MS patients (197), implying that this cytokine may be part of a compensatory response to detrimental inflammation.…”

Molecular Insights Into Regulatory T-Cell Adaptation to Self, Environment, and Host Tissues: Plasticity or Loss of Function in Autoimmune Disease

“…This is mediated by alarmin signaling and induction of tissue-specific tissue repair signals, e.g., amphiregulin. The IL33–ST2 signaling partnership is key to tissue Treg function, where local expression of IL33 or IL1 has opposing effects on Treg polarization and hence function ( 160 – 162 ), giving fine-tuning of Treg function in the tissue in response to injury. There is hence a growing role for tissue-resident Treg, such as VAT Treg ( 163 ); however, some of the tissue repair function is independent of suppressor function ( 7 ).…”

The Prostaglandin D2 Receptor CRTH2 Promotes IL-33–Induced ILC2 Accumulation in the Lung

“…Data are mean 6 SEM, analyzed using a linear fixed effect model with pairwise comparison; data are compiled from three independent experiments; PBS (n = 6), rmIL-33 (n = 8-9). ***p # 0.001. eosinophils and T cells can also be directly regulated by IL-33 via expression of ST2 (20,71) or indirectly by IL-33-mediated activation of other regulatory and/or adhesion factors (72)(73)(74). Furthermore, despite normal eosinophil and CD4 + T cell responses and intact IL-5 and IL-13 production capacity in lung ILC2s (Fig.…”