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Uncovering the cellular heterogeneity and origin of neutrophils at the onset of acute graft-versus-host disease (GVHD) by single-cell RNA-seq

ABSTRACT: Acute graft-versus-host disease (GVHD) is the main cause of morbidity and mortality after allo-HSCT, which is determined by interactions between innate and adaptive immune system. We used single cell RNA sequencing (scRNA-seq) to construct transcriptional profile of immune cells in peripheral blood from patients with or without acute GVHD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227081 | GEO | 2026/03/01

REPOSITORIES: GEO

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GVHD-mediated Vicious Cascade: Impaired Reconstitution of Immunosuppressive Donor Plasmacytoid Dendritic Cells

Project description:In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), severe graft-versus-host disease (GVHD) is tied to failed donor plasmacytoid DC (pDC) reconstitution. The mechanism whereby GVHD causes donor pDC defects and the precise role donor pDCs play in GVHD remain poorly understood. pDCs develop from HSCs in successive stages through Flt3 signaling-dependent differentiation, beginning as multi-potent progenitors (MPPs) and later becoming common DC progenitors. We observed that MPPs were critical for sustaining pDCs and were severely depleted during GVHD. Loss of MPPs was associated with decreased amounts of MPP-producing HSCs and mTOR activation-induced cell death of proliferating MPPs. Additionally, GM-CSF derived from alloreactive T cells subverted MPP production of pDCs. Together, GVHD and alloreactive T cells caused donor pDC defects by impairing the generation, maintenance and differentiation of HSCs and MPPs. Importantly, pDCs suppressed the proliferation and expansion of activated autologous CD4+ T cells via a type I-IFN signaling-dependent mechanism. Transfer of donor pDCs early after transplantation repressed GVHD and preserved potent GVL effects, significantly improving the survival of leukemia mice undergoing allo-HSCT. Our findings identify novel strategies that improve the recovery of donor pDCs early after allo-HSCT and thus may represent an effective therapy to control GVHD. Our findings have broad implications for other diseases in which functional DC development is impaired, such as chronic infections, autoimmunity and cancer.

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Project description:Wildtype (WT) BALB/c mice were treated with allogeneic hematopoietic cell transplantation (allo-HCT) in order to induce acute GVHD. C57BL/6 mice were used bone marrow (BM) and T cell donor mice. We studied the effect of oral hBD-2 treatment versus vehicle (PBS) control treatment on the gene expression in the colon, as main GVHD target organ.

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Targeting Interleukin-2-Inducible T-cell Kinase (ITK) differentiates GVL and GVHD in allo-HSCT

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