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.
Highlights
Allogeneic hematopoietic stem cell transplantation is a lifesaving treatment used for many hematologic malignancies and bone marrow failure syndromes.[1]
Our results show that Tregs from acute graft-versus-host disease (aGVHD) patients exhibited an exhausted phenotype that was characterized by the instability of Foxp[3] expression, decreased suppressor ability, defective migration capacity, and increased apoptosis, which was accompanied by Lkb[1] downregulation
Decreased frequencies of Tregs in Bone marrow (BM) and peripheral blood (PB) from aGVHD patients Previous studies have verified the progressive loss of Tregs in the PB of patients with aGVHD, which is initiated by proinflammatory donor T cells
Summary
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a lifesaving treatment used for many hematologic malignancies and bone marrow failure syndromes.[1]. Marked improvements in immunosuppressive therapies have been achieved, aGVHD is still the primary cause of nonrecurrent death[3] associated with allo-HSCT. Regulatory T cells (Tregs) are generated in the thymus and are evidenced by the expression of CD4, high levels of CD25, and the intracellular expression of the transcription factor Foxp[3], which are crucial for maintaining immune homeostasis via various mechanisms.[4] Tregs have been reported to play an important role in allo-HSCT by suppressing various T cell-associated inflammatory diseases and alleviating GVHD without weakening the graft-versus-leukemia effect.[5] This was initially verified in several murine studies,[6] and it has been exploited in a clinical trial with early encouraging results.[7] Treg-mediated regulation of conventional T cell responses during allogeneic transplantation is a crucial mechanism of peripheral T cell tolerance that has been associated with transplantation tolerance in animal models.[8]
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