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Investigating the trafficking and interactions of the pre-T cell receptor complex
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Garforth, Sam (2023) Investigating the trafficking and interactions of the pre-T cell receptor complex. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3929635
Abstract
T cells must pass through several checkpoints during their development in the thymus, beginning with selection of cells that have productively rearranged the TCRβ gene. Thymocytes are rescued from apoptosis at this checkpoint by transient surface expression of the pre-TCR, a complex of the expressed TCRβ chain and the invariant pTα chain. Whilst pre-TCR signalling initiates commitment to the αβ-lineage, signalling from the structurally similar ϒδTCR, or premature expression of the αβTCR, instead biases cells towards the ϒδ-lineage. How thymocytes cells can distinguish between the signalling initiated from these receptors is still unclear.
This work reconstitutes pre-TCR expression in a non-immune system, allowing the trafficking of the receptor to be studied in detail without the effects of receptor signalling. I find the low surface expression of the pre-TCR is a consequence of poor complex assembly and lysosomal degradation. I also present evidence that low surface expression of the pre-TCR produces a weak but distinct tonic signal. This might enable the receptor to be distinguished from the TCR at the _-selection checkpoint.
This work also investigates TMEM131, a highly conserved but poorly characterised membrane protein, previously identified as a pre-TCR interaction partner. Data presented here is consistent with TMEM131 acting as an ER chaperone. TMEM131 is directed to the ER by its signal peptide and is retained by a sequence in its C-terminal tail. The cytoplasmic tail of TMEM131 appears to be cleaved at multiple sites which I attribute to partial degradation by the proteasome. I applied a BioID assay to identify additional interaction partners and clients of TMEM131.
I have initiated work to make a TMEM131 knockout in Zebrafish in order to study the function of the protein during development.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QR Microbiology Q Science > QR Microbiology > QR180 Immunology |
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Library of Congress Subject Headings (LCSH): | T cells, T cells -- Receptors, Membrane proteins, Cellular immunity | ||||
Official Date: | January 2023 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | James, John R. | ||||
Format of File: | |||||
Extent: | 256 pages : colour illustrations | ||||
Language: | eng |
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