Characterization of Thymic Progenitors in Adult Mouse Bone Marrow

Perry, S. Scott; Pierce, Lauren; Slayton, William B.; Spangrude, Gerald J.

doi:10.4049/jimmunol.170.4.1877

Cited by 46 publications

(48 citation statements)

References 27 publications

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“…Similar results have been reported in mice, in that bone marrow transplantation into irradiated recipient mice led to full reconstitution of the immune system (40). However, transplantation of thymus cells could only transiently reconstitute the thymic compartment (41). Our experiments in the zebrafish indicate that hematopoietic cells in the kidney marrow give rise to T cell progenitors that migrate to the thymus throughout life.…”

Section: Discussionsupporting

confidence: 74%

In vivo tracking of T cell development, ablation, and engraftment in transgenic zebrafish

Langenau

Ferrando²,

Traver³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

401

380

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Transgenic zebrafish that express GFP under control of the T cell-specific tyrosine kinase (lck) promoter were used to analyze critical aspects of the immune system, including patterns of T cell development and T cell homing after transplant. GFP-labeled T cells could be ablated in larvae by either irradiation or dexamethasone added to the water, illustrating that T cells have evolutionarily conserved responses to chemical and radiation ablation. In transplant experiments, thymocytes from lck-GFP fish repopulated the thymus of irradiated wild-type fish only transiently, suggesting that the thymus contains only short-term thymic repopulating cells. By contrast, whole kidney marrow permanently reconstituted the T lymphoid compartment of irradiated wild-type fish, suggesting that long-term thymic repopulating cells reside in the kidney.T he zebrafish has emerged as an important vertebrate genetic model of development. Zebrafish embryos are transparent and develop rapidly ex utero, and most organ systems are fully developed by 5 days postfertilization (dpf). Forward genetic screens in the zebrafish have been instrumental in identifying gene mutations that affect development (1-3). Such genetic approaches have been used successfully to identify genes involved in patterning, regeneration, and the development of organs, including heart, eye, and blood (4, 5). Additionally, small-molecule-based screens in the zebrafish have identified chemicals that perturb normal development (6, 7), and drug screens have been proposed to identify compounds that suppress cancer-associated phenotypes (8-10).Comparisons of fish and mammalian hematopoiesis indicate that the genetic programs underlying vertebrate blood development have been highly conserved throughout evolution (5). Like their mammalian counterparts, fish B cells express Ig proteins, and T cells express T cell receptor components (11); both of which require gene rearrangements mediated by the rag1 and rag2 proteins (12). Moreover, many homologs of the mammalian lymphocyte receptors have been identified in fish, including CD3 (13) and the CD8 coreceptor (14). Taken together, these findings suggest that T and B cell development in the fish relies on many of the same molecules and pathways used in mammalian lymphopoiesis (15,16).The development and functional anatomy of the thymus are also remarkably similar between fish and humans. The zebrafish thymic rudiment is completely developed by 60 h postfertilization (hpf) and by 68 hpf is colonized by T lymphocyte progenitors, which begin to transcribe rag1 and rag2 by 72 hpf (15,(17)(18)(19). As in mice and humans, mature T cells localize to the medulla of the adult zebrafish thymus, whereas immature T cells localize to the cortex (20).The genetics underlying the development of the zebrafish lymphoid system is under active investigation, but functional studies of the zebrafish immune system have been limited by the lack of tools to facilitate the isolation and characterization of different lymphoid cell populations. For example, a...

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Section: Discussionsupporting

confidence: 74%

In vivo tracking of T cell development, ablation, and engraftment in transgenic zebrafish

Langenau

Ferrando²,

Traver³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

401

380

View full text Add to dashboard Cite

show abstract

“…These results suggest ELPs may turn out to be a heterogeneous progenitor pool, with separate progenitors possessing T or B lineage potential. Consistent with such a perspective, recent work (in Thy1.1 mice only) has identified a Thy1.1 Ϫ BM LSK population that possesses efficient T progenitor activity but inefficient B and myeloid progenitor activity (53).…”

Section: Lymphoid Specification In Elpsmentioning

confidence: 49%

Early T Lineage Progenitors: New Insights, but Old Questions Remain

Bhandoola

Sambandam

Allman

et al. 2003

The Journal of Immunology

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“…Other findings also strongly support continued translational studies for the development of IT -based HSC transplantation strategies including: (a) a significantly more rapid kinetics of T-cell reconstitution following IT as compared to IV administration of HSC and (b) long-term thymopoiesis by IT-injected precursors in nonconditioned recipients, even across histocompatibility barriers (Fig. 2) [23,41,57,[60][61][62]. It will therefore be important to determine the clinical settings in which an IT transplantation approach, potentially enhancing HSC differentiation to a T lineage fate, will improve short-as well as long-term patient outcome.…”

Section: Future Perspectivesmentioning

confidence: 82%

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

2013

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Allogeneic hematopoietic stem cell (HSC) transplantation can cure patients suffering from diverse genetic and acquired diseases as well as cancers. Nevertheless, under conditions where T-cell reconstitution is critical, the entry of donor progenitors into the thymus remains a major bottleneck. It is assumed that following the intravenous injection of HSC, they first home to the BM. More committed progenitors can then be exported to the thymus in response to a myriad of signals regulating thymus seeding. Notably although, the thymus is not continually receptive to the import of hematopoietic progenitors. Furthermore, as stem cells with self-renewing capacity do not take up residence in the thymus under physiological conditions, the periodic colonization of the thymus is essential for the sustained differentiation of T lymphocytes. As such, we and others have invested significant efforts into exploring avenues that might foster a long-term thymus-autonomous differentiation. Here, we review strategic approaches that have resulted in long-term T-cell differentiation in immunodeficient (SCID) mice, even across histocompatibility barriers. These include the forced thymic entry of BM precursors by their direct intrathymic injection as well as the transplantation of neonatal thymi. The capacity of the thymus to support hematopoietic progenitors with renewal potential will hopefully promote the development of new therapeutic strategies aimed at enhancing T-cell differentiation in patients undergoing HSC transplantation.

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Characterization of Thymic Progenitors in Adult Mouse Bone Marrow

Cited by 46 publications

References 27 publications

In vivo tracking of T cell development, ablation, and engraftment in transgenic zebrafish

In vivo tracking of T cell development, ablation, and engraftment in transgenic zebrafish

Early T Lineage Progenitors: New Insights, but Old Questions Remain

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

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