Key Points
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The adult thymus requires input from haematopoietic progenitors in the bone marrow to maintain T-cell development. These progenitors colonize the thymus through the blood.
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Models suggesting that T cells are uniquely derived from common lymphoid progenitors (CLPs) are likely to be inadequate. Instead, multiple bone-marrow progenitors are T-cell-lineage competent, and might contribute to intrathymic T-cell development.
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Early T-cell progenitors (ETPs) in the adult thymus can be minimally defined as lineage (Lin)lowCD25−KIThi. However, differential expression of CD24, enhanced green fluorescent protein (EGFP) in reporter mice in which EGFP expression is controlled from the CC-chemokine receptor 9 (Ccr9) locus (CCR9–EGFP), and fms-related tyrosine kinase 3 (FLT3) by the ETP population indicates further heterogeneity.
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The developmental potential of FLT3+ETPs and CCRP–EGFPhi ETPs indicates that these cells are developmentally early ETPs, and that thymus-settling cells express FLT3 and CCR9.
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Haematopoietic stem cells (HSCs) and FLT3-expressing multipotential progenitors (MPPs) are present in the blood, and so are available to settle in the thymus. MPPs are likely to contain physiologically relevant thymus-settling progenitors.
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The ability of T-cell-lineage-competent haematopoietic progenitors to contribute to the T-cell lineage depends on their ability to leave the bone marrow and to migrate to and settle in the thymus, as well as on their ability to expand after thymus settling. It does not depend on their degree of prethymic restriction to the T-cell lineage.
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Important goals for the future include identifying the signals required for the migration of bone-marrow progenitors to the thymus, and determining the contribution of different bone-marrow progenitors to early T-cell-progenitor populations. Whether different progenitors dominate at different developmental stages or in different circumstances, and why, are important unanswered questions in the field.
Abstract
T cells developing in the adult thymus ultimately derive from haematopoietic stem cells in the bone marrow. Here, we summarize research into the identity of the haematopoietic progenitors that leave the bone marrow, migrate through the blood and settle in the thymus to generate T cells. Accumulating data indicate that various different bone-marrow progenitors are T-cell-lineage competent and might contribute to intrathymic T-cell development. Such developmental flexibility implies a mechanism of T-cell-lineage commitment that can operate on a range of T-cell-lineage-competent progenitors, and further indicates that only those T-cell-lineage-competent progenitors able to migrate to, and settle in, the thymus should be considered physiological T-cell progenitors.
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Acknowledgements
We thank E. V. Rothenberg and members of the Bhandoola laboratory for their critical comments. The Bhandoola laboratory is supported by grants from the National Institutes of Health and the Commonwealth of Pennsylvania.
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Glossary
- Parabiotic mice
-
The circulation of two mice is joined surgically through a flap of skin.
- Pre-pro-B cell
-
The pre-pro-B-cell population is another term for lymphoid progenitors in Hardy Fraction A, which contains CLP-2s.
- Hardy Fraction
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B cells and B-cell progenitors were divided into Fractions A, B, C, C', D, E and F based on cell-surface expression of B220, CD43, CD24, BP1, IgD and IgM by R. R. Hardy.
- Methylcellulose assays
-
In these assays, progenitor cells are added to methylcellulose medium that contains cytokines. The mixture is plated and incubated for several days. The number and type of colonies resulting from growth of different progenitors is studied. This assay supports myeloid-, erythroid- and B-cell-lineage development, but does not support T-cell-lineage development.
- RAG-reporter mice
-
Two different RAG (recombination-activating gene)-reporter mice have been used in studies of lymphocyte development. One transgenic mouse line expresses green fluorescent protein (GFP) under the control of endogenous Rag1 locus control elements. The other transgenic mouse line carries a bacterial artificial chromosome that encodes a GFP reporter under the control of Rag2 locus control elements.
- pTα reporter mice
-
Pre-T-cell-receptor α-chain (pTα) reporter mice are transgenic mice that express the human CD25 cell-surface marker under the control of locus control elements of the gene encoding pTα.
- Lunatic fringe glycosyltransferase
-
Lunatic fringe is a glycosyltransferase that can modify the extracellular domain of the Notch receptor, thereby altering Notch interactions with its ligands.
- OP9–DL1 stromal cells
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OP9 bone-marrow cell lines derived from Mscsfop/Mscsfop mice (these cells do not produce functional macrophage colony-stimulating factor (M-CSF)) were engineered to express the Notch ligand Delta-like 1 (DL1) in Juan Carlos Zúñiga-Pflücker's laboratory. These engineered stromal cells support T-cell development in in vitro cultures to the CD4+CD8+ stage, and are very useful for studies of T-cell development.
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Bhandoola, A., Sambandam, A. From stem cell to T cell: one route or many?. Nat Rev Immunol 6, 117–126 (2006). https://doi.org/10.1038/nri1778
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DOI: https://doi.org/10.1038/nri1778
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