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Published on: January 12, 2015
FOXN1 mutation abrogates prenatal T-cell development in humans
I Vigliano1, M Gorrese, A Fusco
1Department of Pediatrics, 'Federico II' University, Via Pansini, 5, Naples 80131, Italy. pignata@unina.it
Background:
The transcription factor FOXN1 is implicated in the differentiation of thymic and skin epithelial cells, and alterations in it are responsible for the Nude/SCID phenotype. During a genetic counselling programme offered to couples at risk in a community where a high frequency of mutated FOXN1 had been documented, the identification of a human FOXN1(-/-) fetus gave the unique opportunity to study T cell development in utero.
Results:
Total blockage of CD4(+) T cell maturation and severe impairment of CD8(+) cells were documented. Evaluation of the variable-domain β-chain (Vβ) families' usage among T lymphocytes revealed that the generation of T cell receptor (TCR) diversity occurred to some extent in the FOXN1(-/-) fetus, although it was impaired compared with the control. A few non-functional CD8(+) cells, mostly bearing TCRγδ in the absence of CD3, were found.
Discussion:
FOXN1 is crucial for in utero T cell development in humans. The identification of a limited number of CD8(+) cells suggests an extrathymic origin for these cells, implying FOXN1-independent lymphopoiesis.
Insights
The transcription factor FOXN1 is essential for human T cell development in the womb. Its absence blocks CD4(+) T cell maturation and impairs CD8(+) cells, suggesting extrathymic origins for some lymphocytes.
Area of Science:
- Immunology
- Developmental Biology
- Genetics
Background:
- The transcription factor FOXN1 plays a key role in thymic and skin epithelial cell differentiation.
- Mutations in FOXN1 cause the Nude/Severe Combined Immunodeficiency (SCID) phenotype.
- A unique opportunity arose to study T cell development in a FOXN1(-/-) human fetus.
Purpose of the Study:
- To investigate the role of FOXN1 in human in utero T cell development.
- To analyze T cell maturation and T cell receptor (TCR) diversity in a FOXN1-deficient fetus.
Main Methods:
- Analysis of T cell populations (CD4+, CD8+) in a FOXN1(-/-) fetus.
- Evaluation of T cell receptor (TCR) variable-domain β-chain (Vβ) family usage.
- Assessment of CD3 and TCRγδ expression on T lymphocytes.
Main Results:
- Complete blockage of CD4(+) T cell maturation was observed.
- Severe impairment of CD8(+) T cell development occurred.
- TCR diversity generation was present but impaired; some non-functional CD8(+) cells with TCRγδ were found.
Conclusions:
- FOXN1 is critical for T cell development during human gestation.
- The presence of limited CD8(+) cells suggests a FOXN1-independent pathway for lymphopoiesis, potentially extrathymic.
