Intrathymic expression of Flt3 ligand enhances thymic recovery after irradiation

Kenins, Linda; Gill, Jason; Boyd, Richard; Holländer, Georg A.; Wodnar-Filipowicz, Aleksandra

doi:10.1084/jem.20072065

Cited by 52 publications

(51 citation statements)

References 32 publications

(47 reference statements)

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“…Flt3-L induces mTOR activation (32) and is required both during the differentiation of early hematopoietic precursors in the bone marrow (33) and during the final steps of DC differentiation in peripheral organs (16,29). Earlier studies have shown that Flt3-L is produced by a variety of different organs and cell lines (34)(35)(36)(37)(38)(39), but little is known about its in vivo distribution.…”

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confidence: 99%

Organ-Specific Cellular Requirements for In Vivo Dendritic Cell Generation

Miloud

Fiegler

Suffner

et al. 2012

The Journal of Immunology

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Bone marrow-derived dendritic cell (DC) precursors seed peripheral organs, where they encounter diverse cellular environments during their final differentiation into DCs. Flt3 ligand (Flt3-L) is critical for instructing DC generation throughout different organs. However, it remains unknown which cells produce Flt3-L and, importantly, which cellular source drives DC development in such a variety of organs. Using a novel BAC transgenic Flt3-L reporter mouse strain coexpressing enhanced GFP and luciferase, we show ubiquitous Flt3-L expression in organs and cell types. These results were further confirmed at the protein level. Although Flt3-L was produced by immune and nonimmune cells, the source required for development of the DC compartment clearly differed among organs. In lymphoid organs such as the spleen and bone marrow, Flt3-L production by hemopoietic cells was critical for generation of normal DC numbers. This was unexpected for the spleen because both immune and nonimmune cells equally contributed to the Flt3-L content in that organ. Thus, localized production rather than the total tissue content of Flt3-L in spleen dictated normal splenic DC development. No differences were observed in the number of DC precursors, suggesting that the immune source of Flt3-L promoted pre-cDC differentiation in spleen. In contrast, DC generation in the lung, kidney, and pancreas was mostly driven by nonhematopoietic cells producing Flt3-L, with little contribution by immune cells. These findings demonstrate a high degree of flexibility in Flt3-L–dependent DC generation to adapt this process to organ-specific cellular environments encountered by DC precursors during their final differentiation.

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confidence: 99%

Organ-Specific Cellular Requirements for In Vivo Dendritic Cell Generation

Miloud

Fiegler

Suffner

et al. 2012

The Journal of Immunology

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“…Grafted B6 lobes expressed FL on MTS15 1 stromal cells (Fig. 5B), at a level comparable to that of steady-state B6 adult thymi [26]. Total thymic cell count was similar in both grafts (Fig.…”

Section: Importance Of Intrathymic Fl In Steady-state Thymopoiesis Ismentioning

confidence: 79%

“…In the thymus, Flt3 is expressed by a subset of ETP, and these Flt3 1 ETP represent the earliest intrathymic T lineage progenitors identified thus far [24]. We have recently shown that following irradiation Flt3 ligand (FL) is upregulated by peri-vascular fibroblasts in the thymus, and this enhances thymic recovery [26]. These results indicate that the expression of the Flt3 receptor on a sub-population of ETP is functionally relevant in an immune reconstitution setting.…”

Section: Introductionmentioning

confidence: 80%

“…Previously, we have shown that availability of high intrathymic FL levels is important for the reconstitution of thymic precursors 7 and 10 days after lethal irradiation and BMT [26]. Here, we examined whether FL-Flt3 interactions play a role in T-cell progenitor development in steady-state thymopoiesis.…”

Section: Flt3 Receptor Expression On T-cell Progenitors Is Important mentioning

confidence: 99%

“…We have recently shown that FL is expressed by thymic MTS15 1 fibroblasts and its expression increases following irradiation [26].…”

Section: Fl Expression By Thymic Stromal Cells Is Upregulated Upon Thmentioning

confidence: 99%

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