The IL-33/ST2 axis augments effector T-cell responses during acute GVHD

Area of Science:

• Immunology
• Transplantation Immunology
• Inflammation Research

Background:

• Interleukin-33 (IL-33) binding to its receptor, suppression of tumorigenicity 2 (ST2), has dual effects.
• Elevated soluble ST2 (sST2) levels indicate steroid-refractory graft-versus-host disease (GVHD) and mortality.
• The immunomodulatory role of sST2 in GVHD remained unclear.

Purpose of the Study:

• To investigate the role of the IL-33/ST2 axis in GVHD pathogenesis.
• To determine if sST2 acts as an immune modulator or solely as a biomarker in GVHD.
• To explore the IL-33/ST2 axis as a potential therapeutic target for GVHD.

Main Methods:

• Assessed IL-33 production in mice and human GVHD patients.
• Administered exogenous IL-33 and utilized il33(-/-) recipient mice.
• Examined ST2 expression on T cells and used st2(-/-) donor T cells in murine GVHD models.
• Investigated the effect of ST2-Fc infusions on GVHD lethality.

Main Results:

• Increased IL-33 production observed in the GI tract during GVHD.
• Exogenous IL-33 exacerbated GVHD, while il33(-/-) recipients showed reduced lethality and TNF-α production.
• ST2 upregulation on alloreactive T cells and increased sST2 correlated with GVHD progression.
• st2(-/-) donor T cells significantly reduced GVHD lethality and GI pathology.
• ST2-Fc blockade markedly reduced GVHD lethality, confirming ST2's role as a decoy receptor.

Conclusions:

• The IL-33/ST2 axis plays a critical role in modulating GVHD.
• IL-33 exacerbates GVHD, while ST2 acts as a decoy receptor that influences T cell responses.
• Targeting the IL-33/ST2 pathway presents a promising therapeutic strategy for preventing and treating GVHD.