Single-Cell Transcriptomics Reveals Discrete Steps in Regulatory T Cell Development in the Human Thymus.

Autor:	Morgana F; Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands.; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands., Opstelten R; Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands.; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands., Slot MC; Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands.; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands., Scott AM; Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.; School of Cancer Medicine, La Trobe University, Melbourne, Australia., van Lier RAW; Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands.; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands., Blom B; Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands., Mahfouz A; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.; Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands; and., Amsen D; Department of Hematopoiesis, Sanquin Research, Amsterdam, the Netherlands; d.amsen@sanquin.nl.; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands.; Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, the Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2022 Jan 15; Vol. 208 (2), pp. 384-395. Date of Electronic Publication: 2021 Dec 22.
DOI:	10.4049/jimmunol.2100506
Abstrakt:	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. (Copyright © 2022 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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