Allogeneic hematopoietic stem cell transplantation promotes aGVHD via IL-33/IL-5/Foxp3 axis

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, driven by dysregulated T cell activation and differentiation. This study investigated the roles of the interleukin-33/interleukin-5/Foxp3 axis in aGVHD. Serum interleukin-5 levels were measured in 79 patients with different aGVHD statuses. In vitro, naive CD4 positive T cells were cultured under various conditions to assess the effects of interleukin-33 and interleukin-5 modulation on T cell differentiation. In vivo, aGVHD mouse models were established to evaluate disease severity, immune cell differentiation, and inflammatory responses following over-expression of interleukin-33 or interleukin-5. Interleukin-5 levels were significantly elevated in patients with steroid-sensitive aGVHD and further increased after the combination therapy. Interleukin-33 up-regulated interleukin-5 and down-regulated Foxp3 expression, promoting differentiation toward pro-inflammatory T cell subsets while reducing the number of regulatory T cells. Silencing of interleukin-5 reversed these effects. In mice, over-expression of interleukin-33 or interleukin-5 aggravated tissue injury, enhanced inflammatory responses, and altered T cell differentiation. The interleukin-33/interleukin-5 axis exacerbates aGVHD severity by modulating Foxp3 and T cell differentiation, highlighting a potential therapeutic target.