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Single-cell characterization of immune aplastic anemia reveals convergence of adaptive and innate immunity: in vitro

ABSTRACT: Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by combining scRNA+TCRαβ-seq, TCRβ-seq, flow cytometry and plasma cytokine profiling of >250 patients with AA, >250 patients with other hematological disorders and >1,000 healthy controls, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRB-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRαβ-seq readout utilizing primary HSPCs and immune cells (in total 55 conditions) provide evidence that NK cells alone cannot kill HSPCs, but sensitize them to CD8+ T cell mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. To conclude, our results reveal convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell mediated autoimmunity.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

SUBMITTER: Jani Huuhtanen

PROVIDER: E-MTAB-13484 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Single-cell characterization of immune aplastic anemia reveals convergence of adaptive and innate immunity: in vivo

Project description:Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by combining scRNA+TCRαβ-seq, TCRβ-seq, flow cytometry and plasma cytokine profiling of >250 patients with AA, >250 patients with other hematological disorders and >1,000 healthy controls, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRB-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRαβ-seq readout utilizing primary HSPCs and immune cells (in total 55 conditions) provide evidence that NK cells alone cannot kill HSPCs, but sensitize them to CD8+ T cell mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. To conclude, our results reveal convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell mediated autoimmunity.

2024-12-12 | E-MTAB-13485 | biostudies-arrayexpress

Functional single-cell characterization of immune aplastic anemia shows convergence of NK and NK-like CD8+ T cells with disease-associated TCR signature

Project description:Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by analyzing an international cohort of 156 AA patients with scRNA+TCRÃŽÂ±ÃŽÂ²-seq, TCRÃŽÂ²-seq, flow cytometry, and plasma cytokine profiling with comparisons to healthy controls and patients with other hematological disorders, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRÃŽÂ²-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRÃŽÂ±ÃŽÂ²-seq readout utilizing primary HSPCs and immune cells provide evidence that NK cellscannot kill HSPCs alone, but sensitize them to CD8+ T cell-mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. Our results reveal the convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell-mediated autoimmunity.

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Functional single-cell characterization of immune aplastic anemia shows convergence of NK and NK-like CD8+ T cells with disease-associated TCR signature

Project description:Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by analyzing an international cohort of 156 AA patients with scRNA+TCRÃŽÂ±ÃŽÂ²-seq, TCRÃŽÂ²-seq, flow cytometry, and plasma cytokine profiling with comparisons to healthy controls and patients with other hematological disorders, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRÃŽÂ²-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRÃŽÂ±ÃŽÂ²-seq readout utilizing primary HSPCs and immune cells provide evidence that NK cellscannot kill HSPCs alone, but sensitize them to CD8+ T cell-mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. Our results reveal the convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell-mediated autoimmunity.

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2021-11-26 | E-MTAB-11170 | biostudies-arrayexpress

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2013-04-15 | E-MTAB-1611 | biostudies-arrayexpress

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2020-04-03 | PXD014894 | Pride

Andersson_et_al_2013

Project description:LGL leukemia is chronic clonal lymphoproliferative disorder, characterized by expansion of cytotoxic CD8+ T-cells or NK-cells. We compared gene expression of 2 LGL leukemia patients with STAT3 mutation (Patients 11 and 12) and 2 LGL leukemia patients without STAT3/STAT5b mutation (Patients 9 and 10) with CD8 and CD4 samples from healthy controls to assess different gene expression patterns between samples.

2013-11-14 | E-MTAB-2068 | biostudies-arrayexpress

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Project description:Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used widely to activate the immune system against tumor cells. Despite their therapeutic benefits, ICIs are known to cause immune-related adverse events (irAE) such as myocarditis, a rare but serious side effect with up to 50% mortality. To identify pathogenic immune subset(s) responsible for ICI myocarditis and other irAE, we performed single cell mass cytometry (CyTOF) on peripheral blood mononuclear cells from 40 patients and controls with irAE including four patients with ICI myocarditis. We also profiled 15 patients/controls using single cell RNA sequencing (scRNA-seq) with feature barcoding for surface marker expression confirmation. In both CyTOF/scRNAseq analyses, we found expansions of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in ICI myocarditis patients compared to controls. Using T cell receptor sequencing, we demonstrated a significant clonal expansion of CD8+ Temra cells in myocarditis patients. Transcriptomic profiling of these Temra CD8+ clones confirmed their highly activated and cytotoxic phenotype with expression of granzyme/perforin. Longitudinal data revealed the progression of these Temra CD8+ cells into an exhausted phenotype two months after diagnosis of myocarditis and after treatment with glucocorticoids. Differential expression of several proinflammatory chemokines (CCL4/CCL4L2/CCL5) was uncovered in the clonally expanded Temra CD8+ cells and ligand-receptor analysis implicated their regulation of other inflammatory cells such as monocytes and NK cells. These data suggest that the therapeutic modulation of these chemokines may serve as an attractive strategy for reducing life-threatening irAE in ICI-treated cancer patients.

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