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Role of the E3 Ligase Hrd1 in T cell Differentiation and Function
Başlık:
Role of the E3 Ligase Hrd1 in T cell Differentiation and Function
Yazar:
Xu, Yuanming, author.
ISBN:
9780438117419
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (154 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Deyu Fang Committee members: Melissa A. Brown; Steve D. Miller; Chyung-Ru Wang.
Özet:
Disruptive T cell balance is widely observed in immune-based diseases, such as autoimmunity and cancer. Identification of key regulators for T cell immunity is therefore critical for developing novel potential therapeutic targets. Here, I show that genetic hrd1 deletion inhibited T-cell proliferation, production of IL-2, and differentiation into T helper (Th)1 and Th17 cells, and consequently protected mice and human from autoimmune disease. On the other hand, Hrd1 is also required for the integrity and functions of T regulatory cells (Tregs), a major negative immune regulator that maintains immune homeostasis by limiting autoimmune and inflammatory responses. Therefore, mice with Tregs-specific ablation of Hrd1 displayed massive multi-organ lymphocyte infiltration, body weight loss, and the development of severe small intestine inflammation with aging. Taken together, these findings indicate that Hrd1 is crucial to maintain both T effector and Treg cell function and differentiation. Given that Hrd1 is upregulated upon TCR stimulation, and both the conventional and regulatory T cells are developed from the same pool of thymocyte progenitor cells, we were curious about how engagement of the same E3 ligase in these two related cell types execute such different mechanisms. We found that in T effector cells, Hrd1 facilitated T-cell growth through degradation of cyclin-CDK inhibitor p27kip1, and deletion of p27kip1 in Hrd1-null T-cells rescued their defect in proliferation. While in Tregs, the deletion of Hrd1 led to up-regulation of the ER stress sensor, IRE1alpha, and specific inhibition of IRE1alpha kinase rescued impaired Treg induction by Hrd1 deletion. Therefore, Hrd1 functions in a cell-type specific manner and the microenvironment of each cell type determines the specificity of Hrd1 target proteins and their interactions.
Notlar:
School code: 0163
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(694084.1) | 694084-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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