TY - JOUR
T1 - Identification of human exTreg cells as CD16+CD56+ cytotoxic CD4+ T cells
AU - Freuchet, Antoine
AU - Roy, Payel
AU - Armstrong, Sujit Silas
AU - Oliaeimotlagh, Mohammad
AU - Kumar, Sunil
AU - Orecchioni, Marco
AU - Ali, Amal J.
AU - Khan, Amir
AU - Makings, Jeffrey
AU - Lyu, Qingkang
AU - Winkels, Holger
AU - Wang, Erpei
AU - Durant, Christopher
AU - Ghosheh, Yanal
AU - Gulati, Rishab
AU - Nettersheim, Felix
AU - Ley, Klaus
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/10
Y1 - 2023/10
N2 - In atherosclerosis, some regulatory T (Treg) cells become exTreg cells. We crossed inducible Treg and exTreg cell lineage-tracker mice (FoxP3 eGFP−Cre-ERT2 ROSA26 CAG-fl-stop-fl-tdTomato) to atherosclerosis-prone Apoe −/− mice, sorted Treg cells and exTreg cells and determined their transcriptomes by bulk RNA sequencing (RNA-seq). Genes that were differentially expressed between mouse Treg cells and exTreg cells and filtered for their presence in a human single-cell RNA-sequencing (scRNA-seq) panel identified exTreg cell signature genes as CST7, NKG7, GZMA, PRF1, TBX21 and CCL4. Projecting these genes onto the human scRNA-seq with CITE-seq data identified human exTreg cells as CD3+CD4+CD16+CD56+, which was validated by flow cytometry. Bulk RNA-seq of sorted human exTreg cells identified them as inflammatory and cytotoxic CD4+T cells that were significantly distinct from both natural killer and Treg cells. DNA sequencing for T cell receptor-β showed clonal expansion of Treg cell CDR3 sequences in exTreg cells. Cytotoxicity was functionally demonstrated in cell killing and CD107a degranulation assays, which identifies human exTreg cells as cytotoxic CD4+T cells.
AB - In atherosclerosis, some regulatory T (Treg) cells become exTreg cells. We crossed inducible Treg and exTreg cell lineage-tracker mice (FoxP3 eGFP−Cre-ERT2 ROSA26 CAG-fl-stop-fl-tdTomato) to atherosclerosis-prone Apoe −/− mice, sorted Treg cells and exTreg cells and determined their transcriptomes by bulk RNA sequencing (RNA-seq). Genes that were differentially expressed between mouse Treg cells and exTreg cells and filtered for their presence in a human single-cell RNA-sequencing (scRNA-seq) panel identified exTreg cell signature genes as CST7, NKG7, GZMA, PRF1, TBX21 and CCL4. Projecting these genes onto the human scRNA-seq with CITE-seq data identified human exTreg cells as CD3+CD4+CD16+CD56+, which was validated by flow cytometry. Bulk RNA-seq of sorted human exTreg cells identified them as inflammatory and cytotoxic CD4+T cells that were significantly distinct from both natural killer and Treg cells. DNA sequencing for T cell receptor-β showed clonal expansion of Treg cell CDR3 sequences in exTreg cells. Cytotoxicity was functionally demonstrated in cell killing and CD107a degranulation assays, which identifies human exTreg cells as cytotoxic CD4+T cells.
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U2 - 10.1038/s41590-023-01589-9
DO - 10.1038/s41590-023-01589-9
M3 - Article
C2 - 37563308
AN - SCOPUS:85167518306
SN - 1529-2908
VL - 24
SP - 1748
EP - 1761
JO - Nature Immunology
JF - Nature Immunology
IS - 10
ER -