IFN-γ induces acute graft-versus-host disease by promoting HMGB1-mediated nuclear-to-cytoplasm translocation and autophagic degradation of p53.

Abstract

Acute graft-versus-host disease (aGVHD) poses a significant impediment to achieving a more favourable therapeutic outcome in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our prior investigations disclosed a correlation between p53 down-regulation in CD4+ T cells and the occurrence of aGVHD. Notably, the insufficiency of the CCCTC-binding factor (CTCF) emerged as a pivotal factor in repressing p53 expression. However, the existence of additional mechanisms contributing to the reduction in p53 expression remains unclear. Interferon (IFN)-γ, a pivotal proinflammatory cytokine, assumes a crucial role in regulating alloreactive T-cell responses and plays a complex part in aGVHD development. IFN-γ has the capacity to induce autophagy, a vital catabolic process facilitating protein degradation, in various cell types. Presently, whether IFN-γ participates in the development of aGVHD by instigating the autophagic degradation of p53 in CD4+ T cells remains an unresolved question. In the present study, we demonstrated that heightened levels of IFN-γ in the plasma during aGVHD promoted the activation, proliferation, and autophagic activity of CD4+ T cells. Furthermore, IFN-γ induced the nuclear-to-cytoplasm translocation and autophagy-dependent degradation of p53 in CD4+ T cells. The translocation and autophagic degradation of p53 were contingent upon HMGB1, which underwent up-regulation and translocation from the nucleus to the cytoplasm following IFN-γ stimulation. In conclusion, our data unveil a novel mechanism underlying p53 deficiency in CD4+ T cells among aGVHD patients. This deficiency is induced by IFN-γ and relies on autophagy, establishing a link between IFN-γ, HMGB1-mediated translocation, and the autophagic degradation of p53.