Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia
Open Access
- 23 June 2020
- journal article
- research article
- Published by American Society of Hematology in Blood Advances
- Vol. 4 (12), 2611-2616
- https://doi.org/10.1182/bloodadvances.2020001730
Abstract
The study of early T-cell development in humans is challenging because of limited availability of thymic samples and the limitations of in vitro T-cell differentiation assays. We used an artificial thymic organoid (ATO) platform generated by aggregating a DLL4-expressing stromal cell line (MS5-hDLL4) with CD34(+) cells isolated from bone marrow or mobilized peripheral blood to study T-cell development from CD34(+) cells of patients carrying hematopoietic intrinsic or thymic defects that cause T-cell lymphopenia. We found that AK2 deficiency is associated with decreased cell viability and an early block in T-cell development. We observed a similar defect in a patient carrying a null IL2RG mutation. In contrast, CD34(+) cells from a patient carrying a missense IL2RG mutation reached full T-cell maturation, although cell numbers were significantly lower than in controls. CD34(+) cells from patients carrying RAG mutations were able to differentiate to CD4-CD8+ cells, but not to CD3(+)TCR alpha beta(+) cells. Finally, normal T-cell differentiation was observed in a patient with complete DiGeorge syndrome, consistent with the extra-hematopoietic nature of the defect. The ATO system may help determine whether T-cell deficiency reflects hematopoietic or thymic intrinsic abnormalities and define the exact stage at which T-cell differentiation is blocked.This publication has 20 references indexed in Scilit:
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