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Single-cell analysis highlights a population of Th17-polarized CD4+ naïve T cells showing IL6/JAK3/STAT3 activation in pediatric severe aplastic anemia.
- Source :
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Journal of Autoimmunity . Apr2023, Vol. 136, pN.PAG-N.PAG. 1p. - Publication Year :
- 2023
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Abstract
- Acquired aplastic anemia (AA) is recognized as an immune-mediated disorder resulting from active destruction of hematopoietic cells in bone marrow (BM) by effector T lymphocytes. Bulk genomic landscape analysis and transcriptomic profiling have contributed to a better understanding of the recurrent cytogenetic abnormalities and immunologic cues associated with the onset of hematopoietic destruction. However, the functional mechanistic determinants underlying the complexity of heterogeneous T lymphocyte populations as well as their correlation with clinical outcomes remain to be elucidated. To uncover dysfunctional mechanisms acting within the heterogeneous marrow-infiltrating immune environment and examine their pathogenic interplay with the hematopoietic stem/progenitor pool, we exploited single-cell mass cytometry for BM mononuclear cells of severe AA (SAA) patients pre- and post-immunosuppressive therapy, in contrast to those of healthy donors. Alignment of BM cellular composition with hematopoietic developmental trajectories revealed potential functional roles for non-canonically activated CD4+ naïve T cells in newly-diagnosed pediatric cases of SAA. Furthermore, single-cell transcriptomic profiling highlighted a population of Th17-polarized CD4+CAMK4+ naïve T cells showing activation of the IL-6/JAK3/STAT3 pathway, while gene signature dissection indicated a predisposition to proinflammatory pathogenesis. Retrospective validation from our SAA cohort of 231 patients revealed high plasma levels of IL-6 as an independent risk factor of delayed hematopoietic response to antithymocyte globulin-based immunosuppressive therapy. Thus, IL-6 warrants further investigation as a putative therapeutic target in SAA. • Mass cytometry revealed CD4+ naïve T cells with hyperactivated JAK3/STAT3 pathway may be invloved in SAA pathogenesis. • scRNA-seq uncovered CD4+ CAMK4+ naïve T cells were associated with aberrant immune activation in SAA development. • Aberrant activation of the IL6/JAK3/STAT3 pathway were seen in Th17-polarized CD4+ CAMK4+ naïve T cells from pediatric SAA. • High levels of baseline serum cytokine IL-6 predict delayed hematopoietic response to IST in SAA. Th17-polarized naïve T cells with IL6/JAK3/STAT3 activation show putative clinical significance in SAA. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08968411
- Volume :
- 136
- Database :
- Academic Search Index
- Journal :
- Journal of Autoimmunity
- Publication Type :
- Academic Journal
- Accession number :
- 162978992
- Full Text :
- https://doi.org/10.1016/j.jaut.2023.103026