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Unveiling thymic epithelial cell ontogeny: A roadmap to study the microenvironment for T-cell generation and tolerance
Başlık:
Unveiling thymic epithelial cell ontogeny: A roadmap to study the microenvironment for T-cell generation and tolerance
Yazar:
Ribeiro, Ana Rosalina Pereira, author.
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (161 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-07C.
Özet:
T lymphocytes exhibit a highly diverse T-cell receptor (TCR) repertoire that is crucial for their capacity to recognize and mount specific immune responses against foreign antigens. The thymus harbors a unique stromal cellular network that supports T cell development and education, in which thymic epithelial cells (TECs) are the major components. Thymic epithelium is classically divided in cortical (cTEC) and medullary (mTEC) cells and its proper differentiation is critical for the selection of a diverse and self-tolerant T-cell population. Cortical and medullary TECs derive from a common bipotent precursor that exists in both embryonic and postnatal thymus. Yet, the nature and bioavailability of thymic epithelial progenitors (TEPs), as well as the cellular and molecular mechanisms underlying TEC differentiation pathways downstream of the bipotent progenitor are still poorly understood.
In this thesis, using distinct TEC-specific reporter mouse models, in combination with in vitro and in vivo fate mapping strategies, we studied the molecular and cellular interactions that govern TEC differentiation pathways. As a crucial thymopoietic factor, Interleukin-7 (IL-7) is highly expressed within the thymus. Here, we showed that high IL-7 expression determines a specialized cTEC population that gradually declines as result of MHC/peptide-TCR-mediated interactions between TECs and thymocytes during selection. Additionally, we showed that this specialized cTEC subset has the capacity to generate both cTECs and mTECs in the embryonic thymus, indicating that epithelial precursors transverse through the cortical lineage before committing into mTEC.
Furthermore, we documented the emergence of novel mTEC subsets sharing cTEC and mTEC markers in the postnatal thymus, suggesting that mTEC differentiation maight follow distinct routes in the embryonic and postnatal thymus and that the bipotent progenitors reside within the cortical compartment after birth. Accordingly, exploiting clonogenic assays that selectively grow cells with stem-cell capacity, we demonstrated that cTECs appear to be enriched for epithelial progenitors with the ability to generate both epithelial lineages and to improve thymopoiesis in IL-7-deficient mice. Nevertheless, the abundance of corticalresiding TEPs declines with aging.
Together, these results indicate that the cortical compartment harbors the niche of bipotent precursors in the embryonic and early postnatal thymus, which bioavailability declines across life. The homeostasis of this cTEC niche is controlled by continual TCR-mediated lympho-epithelial interactions.
Understanding the mechanisms underlying the establishment of the thymic microenvironment in the early phase of thymic development and its maintenance across life has become one of the major goals to comprehend the generation of a diverse and tolerant T cell population and, ultimately, intervene in cases of disorder.
Notlar:
School code: 5896
Konu Başlığı:
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678858.1) | 678858-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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