Stem cell transplantation (SCT) is a key therapeutic approach to treat those who suffer from blood cancers. SCT aims to re-establish the patient's defective immune system with donor-derived hematopoietic stem cells and provide the graft-versus-leukaemia effect (GVL), whereby donor immune cells target and eliminate malignant cells within the host due to donor/host genetic disparity. However, a major challenge associated with SCT is the onset of Graft-versus-Host-Disease (GVHD), a severe complication characterised by donor alloreactive immunopathology in healthy recipient tissues. This adverse event is primarily attributed to the same genetic disparities that facilitate the GVL effect, highlighting a significant difficulty in the successful application of SCT.
Bhlhe40 is a basic helix-loop-helix (bHLH) transcription factor involved in a range of biological processes, including circadian rhythm regulation, cell differentiation, and immune responses. In the immune system, Bhlhe40 has been shown to influence the function and differentiation of immune cells, including T cells, which play a significant role in the pathology of GVHD. Recent studies have identified Bhlhe40 as an important transcriptional regulator that regulates the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) in CD4+ T cells, playing a key role in mediating pathological damage within the gastrointestinal (GI) tract during GVHD. However, the role of this transcription factor in CD8+ T cells remains unclear and is currently undefined in allotransplantation.
In this study, we identified that the absence of Bhlhe40 in donor CD8+ T cells within the allogeneic SCT setting substantially mitigates the severity of GVHD, characterised by significantly prolonged survival rates and reduced clinical manifestations. This improved clinical outcome was associated with a series of significant immunological changes, including lower expression of pathogenic cytokines linked with T cell activation and cytotoxicity, revealing a reduced cytotoxic and inflammatory response. Also, we observed significant increase in naive T-cells, and lower frequencies of short-lived-effector cells (SLECs) suggesting a tempered immune response that potentially moderates the severity of GVHD. Hence, our findings suggest that Bhlhe40 plays an important role in regulating the pathogenic potential of CD8+ T cells in GVHD, through its influence on T cell differentiation and cytokine production. Thus, this study provides novel insights into the immunoregulatory functions of Bhlhe40 in CD8+ T cells and presents a potential therapeutic target for GVHD treatment.