From murine to human nude/SCID: the thymus, T-cell development and the missing link - PubMed (original) (raw)

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Rosa Romano et al. Clin Dev Immunol. 2012.

Abstract

Primary immunodeficiencies (PIDs) are disorders of the immune system, which lead to increased susceptibility to infections. T-cell defects, which may affect T-cell development/function, are approximately 11% of reported PIDs. The pathogenic mechanisms are related to molecular alterations not only of genes selectively expressed in hematopoietic cells but also of the stromal component of the thymus that represents the primary lymphoid organ for T-cell differentiation. With this regard, the prototype of athymic disorders due to abnormal stroma is the Nude/SCID syndrome, first described in mice in 1966. In man, the DiGeorge Syndrome (DGS) has long been considered the human prototype of a severe T-cell differentiation defect. More recently, the human equivalent of the murine Nude/SCID has been described, contributing to unravel important issues of the T-cell ontogeny in humans. Both mice and human diseases are due to alterations of the FOXN1, a developmentally regulated transcription factor selectively expressed in skin and thymic epithelia.

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Figures

Figure 1

Figure 1

Steps of T-cell development. The lymphoid progenitor cell goes into the thymus through the cortico-medullary junction. DN thymocytes (CD4−CD8−) migrate across the subcapsular region and then the outer cortex. Interaction between DN cells and cTECs generates DP thymocytes (CD3+CD4+CD8+). Positively selected thymocytes interact with mTECs to complete the maturation process. In the medulla, self-reactive thymocytes are deleted, SP (CD3+CD4+or CD3+CD8+) thymocytes are generated, and, eventually, the export of mature T cells from the thymus takes place.

Figure 2

Figure 2

Differential gene expression profile, which modulates the discrete stages of the T-cell development. The lymphoid progenitors, entering into thymus and expressing the markers of HSCs, are primed to Notch and IL-7 signaling until DN1 stage. During the transition DN1/DN2, immature thymocytes lose multilineage potential through the downregulation of genes involved in the differentiation towards other cellular lineages, as PU.1, TAL1, GATA-2, and C/EBP__α_. At the DN2 stage, Myb, GATA-3, HEBalt, GLI-2, and Bcl-11b are upregulated. At the DN3 stage, the genes required for a proper TCR assembly as Rag-1, Rag-2, and pT__α_ are expressed, thus leading to the __β_-selection. Following _β_-selection check-point, DN4 cells are fully committed to the TCR__αβ + T-cell lineage.

Figure 3

Figure 3

Nail dystrophy patterns in subjects carrying heterozygous mutations in FOXN1 gene: (a) koilonychias, (b) canaliform dystrophy, and (c) leukonychia.

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