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Gamma Delta T Cell Surveillance of Pyrophosphate Metabolites as Signals of Cellular Stress
Başlık:
Gamma Delta T Cell Surveillance of Pyrophosphate Metabolites as Signals of Cellular Stress
Yazar:
Gu, Siyi, author.
ISBN:
9780438083905
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (110 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Erin J. Adams; Robert J. Keenan Committee members: Sean Crosson; David A. Drummond.
Özet:
Human Vgamma9Vdelta2 T cells respond to microbial infections as well as certain types of tumors. Initiation of the Vgamma9Vdelta2 T cell response begins with sensing of small, pyrophosphate-containing molecules called phosphoantigens (pAgs) via the intracellular domain of the butyrophilin 3A1 (BTN3A1) molecule. Combining structural, biophysical and cellular approaches, I aim to dissect the molecular mechanism behind pAg-induced T cell activation. Using nuclear magnetic resonance spectrometry, I characterize a global conformational change in the B30.2 intracellular domain of BTN3A1 induced by pAg binding. I also reveal by crystallography two distinct dimer interfaces in the BTN3A1 full-length intracellular (BFI) domain, which lie in close proximity to the pAg-binding pocket and contain clusters of residues that experience major changes of chemical environment upon pAg binding. This suggests that pAg binding affects a preexisting conformation of the BTN3A1 intracellular domain. I then demonstrate that the extracellular domains of BTN3A1 adopt a V-shaped conformation at rest, and that locking them in this resting conformation without perturbing their membrane reorganization properties diminishes pAg-induced T cell activation. Together, these results indicate that a conformational change in BTN3A1 is a key event of pAg sensing that ultimately leads to T cell activation. In addition, I utilized a mass spectrometry-based technique to identify novel molecular players involved in the pAg-induced T cell activation process. I also characterize, biochemically, the interaction of the BTN3A1 B30.2 domain with RhoB GTPase, a regulator involved in BTN3A1 mediated activation. These findings not only broaden and deepen our understanding of the myriad ways in which gammadelta T cells can be activated but also lays a foundation for practical applications such as the development of therapeutics targeting Vgamma9Vdelta2 T cells in certain infectious diseases and cancers.
Notlar:
School code: 0330
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
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XX(690233.1) | 690233-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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