The Potential Genes Mediate the Pathogenicity of Allogeneic CD4⁺T Cell in aGVHD Mouse Model

Abstract

Acute graft-versus-host disease (aGVHD) remains a significant and severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to the occurrence of aGVHD, allo-HSCT significantly increases the mortality rate compared with autologous hematopoietic stem cell transplantation (auto-HSCT). In this study, auto-HSCT and allo-HSCT aGVHD mouse models were built to detect the difference in CD4+ lymphocyte in different tissues based on ribonucleic acid sequencing (RNA-Seq) analysis. Clustering analysis, functional annotation, and pathway enrichment analysis were performed on differentially expressed genes (DEGs). The protein-protein interaction (PPI) network was used to find hub genes. CD4+T cells were activated by MLR and cytokine stimulation. Cells were sorted out by a flow cell sorter. The selected genes were verified by qRT-PCR, histology, and immunofluorescence staining. The GSE126518 GEO dataset was used to verify the hub genes. Enrichment analysis revealed four immune-related pathways that play an important role in aGVHD, including immunoregulatory interactions between a lymphoid and a nonlymphoid cell, chemokine receptors binding chemokines, cytokine and cytokine receptor interaction, and the chemokine signaling pathway. At the same time, with the PPI network, 11 novel hub genes that were most likely to participate in immunoregulation in aGVHD were identified, which were further validated by qRT-PCR and the GSE126518 dataset. Besides, the protein expression level of Cxcl7 was consistent with the sequencing results. In summary, this study revealed that immunoregulation-related DEGs and pathways played a vital role in the onset of aGVHD. These findings may provide some new clues for probing the pathogenesis and treatment of aGVHD.

Multifaceted Roles of Chemokine C-X-C Motif Ligand 7 in Inflammatory Diseases and Cancer

“…CXCL7 has been shown to be involved in the immunomodulatory function of CD4 + T cells in acute GVHD (aGVHD) ( Yu et al, 2021 ). The lower level of CXCL7 expression in CD4 + T cells of allogeneic HSCT mice compared to autologous HSCT was demonstrated by in vitro and in vivo experiments, whose results were consistent with those of RNA sequencing.…”

“…The lower level of CXCL7 expression in CD4 + T cells of allogeneic HSCT mice compared to autologous HSCT was demonstrated by in vitro and in vivo experiments, whose results were consistent with those of RNA sequencing. Pathway enrichment analysis of CD4 + T cell differential genes in autologous and allogeneic HSCT revealed a non-negligible role of a chemokine signaling pathway in the signaling pathways related to immunomodulation related to aGVHD ( Yu et al, 2021 ).…”

“…Furthermore, abnormal production of the CXCL7 chemokine has been identified in many inflammatory diseases, such as acute lung injury/acute respiratory distress syndrome, autoimmune diseases, graft-versus-host disease, and viral infections. However, the exact role of CXCL7 in the pathogenesis of inflammatory diseases is complex ( Hughes-Austin et al, 2013 ; Bdeir et al, 2017 ; Yu et al, 2021 ).…”