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Single-Cell Transcriptomics Reveals Discrete Steps in Regulatory T Cell Development in the Human Thymus.
Morgana, Florencia; Opstelten, Rianne; Slot, Manon C; Scott, Andrew M; van Lier, René A W; Blom, Bianca; Mahfouz, Ahmed; Amsen, Derk.
Afiliación
  • Morgana F; Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands.
  • Opstelten R; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands.
  • Slot MC; Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands.
  • Scott AM; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands.
  • van Lier RAW; Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands.
  • Blom B; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands.
  • Mahfouz A; Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
  • Amsen D; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
J Immunol ; 208(2): 384-395, 2022 01 15.
Article en En | MEDLINE | ID: mdl-34937744
ABSTRACT
CD4+CD25+FOXP3+ regulatory T (Treg) cells control immunological tolerance. Treg cells are generated in the thymus (tTreg) or in the periphery. Their superior lineage fidelity makes tTregs the preferred cell type for adoptive cell therapy (ACT). How human tTreg cells develop is incompletely understood. By combining single-cell transcriptomics and flow cytometry, we in this study delineated three major Treg developmental stages in the human thymus. At the first stage, which we propose to name pre-Treg I, cells still express lineage-inappropriate genes and exhibit signs of TCR signaling, presumably reflecting recognition of self-antigen. The subsequent pre-Treg II stage is marked by the sharp appearance of transcription factor FOXO1 and features induction of KLF2 and CCR7, in apparent preparation for thymic exit. The pre-Treg II stage can further be refined based on the sequential acquisition of surface markers CD31 and GPA33. The expression of CD45RA, finally, completes the phenotype also found on mature recent thymic emigrant Treg cells. Remarkably, the thymus contains a substantial fraction of recirculating mature effector Treg cells, distinguishable by expression of inflammatory chemokine receptors and absence of CCR7. The developmental origin of these cells is unclear and warrants caution when using thymic tissue as a source of stable cells for ACT. We show that cells in the major developmental stages can be distinguished using the surface markers CD1a, CD27, CCR7, and CD39, allowing for their viable isolation. These insights help identify fully mature tTreg cells for ACT and can serve as a basis for further mechanistic studies into tTreg development.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Timo / Diferenciación Celular / Linfocitos T Reguladores / Timocitos Tipo de estudio: Prognostic_studies Límite: Child, preschool / Humans Idioma: En Revista: J Immunol Año: 2022 Tipo del documento: Article País de afiliación: Países Bajos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Timo / Diferenciación Celular / Linfocitos T Reguladores / Timocitos Tipo de estudio: Prognostic_studies Límite: Child, preschool / Humans Idioma: En Revista: J Immunol Año: 2022 Tipo del documento: Article País de afiliación: Países Bajos