Loss of Lkb1 impairs Treg function and stability to aggravate graft-versus-host disease after bone marrow transplantation

Abstract

Accumulating evidence suggests that a reduction in the number of Foxp3 + regulatory T cells (Tregs) contributes to the pathogenesis of acute graft-versus-host disease (aGVHD), which is a major adverse complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the precise features and mechanism underlying the defects in Tregs remain largely unknown. In this study, we demonstrated that Tregs were more dramatically decreased in bone marrow compared with those in peripheral blood from aGVHD patients and that bone marrow Treg defects were negatively associated with hematopoietic reconstitution. Tregs from aGVHD patients exhibited multiple defects, including the instability of Foxp3 expression, especially in response to IL-12, impaired suppressor function, decreased migratory capacity, and increased apoptosis. Transcriptional profiling revealed the downregulation of Lkb1, a previously identified critical regulator of murine Treg identity and metabolism, and murine Lkb1-regulated genes in Tregs from aGVHD patients. Foxp3 expression in human Tregs could be decreased and increased by the knockdown and overexpression of the Lkb1 gene, respectively. Furthermore, a loss-of-function assay in an aGVHD murine model confirmed that Lkb1 deficiency could impair Tregs and aggravate disease severity. These findings reveal that Lkb1 downregulation contributes to multiple defects in Tregs in human aGVHD and highlight the Lkb1-related pathways that could serve as therapeutic targets that may potentially be manipulated to mitigate aGVHD.

Genome-wide bioinformatic analyses predict key host and viral factors in SARS-CoV-2 pathogenesis

“…Vanins are involved in proinflammatory and oxidative processes, and VNN2 plays a role in neutrophil migration by regulating b2 integrin 76 . Downregulated genes included SNX8 , which has been reported in RNA virus-triggered induction of antiviral genes 23 , 77 , and FKBP5 , a regulator of NF-κB activity 78 . These results suggest that SARS-CoV-2 tends to indirectly target specific genes involved in genome replication and host antiviral immune response without eliciting a global change in cellular transcript processing or protein production.…”

Regulatory T Cells in GVHD Therapy

“…Therefore, it is particularly important to enhance FOXP3 expression in Tregs to ensure that they continue to exert immunosuppressive activity under post-transplantation conditions. Our laboratory and others found that liver kinase b1 (LKB1) is essential for maintaining the stability of FOXP3 expression and the suppression capacity of Tregs in murine models by deletion of the gene encoding LKB1 specifically in Tregs (37)(38)(39)(40). We also found that LKB1 may prevent STAT4mediated methylation of the TSDR, ensuring stable FOXP3 expression (37).…”

CD40 Activity on Mesenchymal Cells Negatively Regulates OX40L to Maintain Bone Marrow Immune Homeostasis Under Stress Conditions

“…Indeed, aGVHD patients exhibit a delayed peripheral B-cell recovery that is associated with increased BM T-cell infiltration oriented towards a Th17 activation state ( 32 ). Furthermore, aGVHD patients are characterized by BM Treg defects that are negatively associated with hematopoietic reconstitution ( 33 ).…”