Abstract
Severe aplastic anemia (SAA) is an autoimmune disease characterized by immune-mediated destruction of hematopoietic stem and progenitor cells. Autoreactive CD8+ T cells have been reported as the effector cells; however, the mechanisms regulating their cell activation in SAA remain largely unknown. Here, we performed proteomics and metabolomics analyses of plasma and bone marrow supernatant, together with transcriptional analysis of CD8+ T cells from SAA patients and healthy donors, to find key pathways that are involved in pathogenic CD8+ T-cell activation. We identified 21 differential proteins and 50 differential metabolites in SAA patients that were mainly involved in energy metabolism, complement and coagulation cascades, and HIF-1α signaling pathways. Interestingly, we found that these pathways are also enriched in T cells from SAA patients by analyzing available single-cell RNA sequencing data. Moreover, CD8+ T cells from SAA patients contain a highly activated CD38+ subset, which was increased in the bone marrow of SAA patients and a murine model of SAA. This subset presented enriched genes associated with the glycolysis or gluconeogenesis pathway, HIF-1α signaling pathway, and complement associated pathways, all of which were of importance in T-cell activation. In conclusion, our study reveals new pathways that may regulate CD8+ T-cell activation in SAA patients and provides potential therapeutic targets for SAA treatment.
Highlights
Severe aplastic anemia (SAA) is a bone marrow (BM) failure syndrome that is characterized by the destruction of hematopoietic stem cells (HSCs) and empty BM
We found that glycolysis or gluconeogenesis, cholesterol metabolism, and HIF-1α signaling pathways are closely related to T-cell activation, and we highlighted CD38+CD8+ T cells as a prognostic marker and a potential therapeutic target in AA
We show that the plasma proteome and metabolome of SAA patients differ from those of healthy donors in pathways involved in the T-cell activation, such as glycolysis or gluconeogenesis, cholesterol metabolism, complement, and AA model (n 5); Mann–Whitney test. *p < 0.05, **p < 0.01, ***p < 0.001
Summary
Severe aplastic anemia (SAA) is a bone marrow (BM) failure syndrome that is characterized by the destruction of hematopoietic stem cells (HSCs) and empty BM. Most patients respond to immunosuppressive therapies (ISTs), suggesting an immune mechanism of AA pathogenesis (Scheinberg and Young, 2012). About 30% of patients become tolerant to IST and need further therapies such as BM transplantation (Scheinberg et al, 2014, Rios et al, 2014). Increased BM accumulation of activated T cells that overexpress cytokines IFN-γ and TNF-α and decreased regulatory T cells are observed in AA patients, which are thought to mediate decreased self-renewal and even apoptosis of HSCs (Sloand et al, 2002, Kim et al, 2002; Young, 2018). Previous studies have demonstrated increased HLA-DR+ (Xing et al, 2014, Liu et al, 2014), CD57+ (Giudice et al, 2018, Feng et al, 2018), and CD27+ (Zhao et al, 2019, Zhang et al, 2019) subpopulations of CD8+ T cells in AA patients, indicating an activated phenotype of CD8+ T cells. The pathogenic mechanisms of CD8+ T-cell activation in SAA still need further elucidation
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