Williams, Cayman;
(2022)
Investigating CD28 co-stimulation in the control of human T cell activation.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
PhD Thesis Cayman Williams Deposit .pdf - Accepted Version Download (14MB) | Preview |
Abstract
CD4+ T cell activation requires a minimum of two signals provided by APCs. The first is facilitated by TCR engagement with cognate peptide-loaded MHC and the second by CD28 engagement with CD80 or CD86. Together these signals control an activation threshold, whereby, a minimum quantity of these signals must be provided to activate the cell. Altering the sensitivity of T cells to stimulation and influencing threshold is potentially a factor contributing to disease risk. For example, autoimmune-associated genetic variants are enriched in non-coding gene regulatory elements, which may alter the quantity of different proteins involved in T cell activation pathways. We developed in vitro models of T cell stimulation with the aim of detecting interindividual variation in threshold and measuring the individual contribution of TCR and CD28 to the response. This allowed us to attribute atypical responses to TCR or CD28 (in)sensitivity. These data act as a proof-of-principle pilot study upon which more data can be acquired to understand the impact of genetic variation on variable thresholds. In addition, the activation threshold is thought to differ between Memory and Naive CD4+ T cells. However, the relative contribution of TCR and CD28 for these subsets is currently a subject of debate. Using our in vitro stimulation assays we provide data that support a dominant role for CD28 signalling in Memory T cell biology that contrasts with TCR dominance in Naive T cells. These data provide insight into the basic biology of Memory and Naive activation thresholds which will be useful for understanding how basic T cell functions are induced and how these can be manipulated. Finally, since CTLA4 regulates the availability of the CD28 ligands, CD80 and CD86, we examined how CTLA4 controls the ability of T cells to achieve an activation threshold. Whilst overlapping roles for these ligands have been described, considerable structural differences argue for different mechanisms of action. Our in vitro models suggest that CD86, due its lower affinity, can escape CTLA4 regulation and thereby act as the main ligand providing co-stimulation. In contrast, CD80 appears to protect CD86 from CTLA4 transendocytosis as its higher affinity makes CD80 a dominant target for CTLA4 capture. These data further enhance our understanding regarding the basic mechanisms of co-stimulation and CTLA4 regulation.
Type: | Thesis (Doctoral) |
---|---|
Qualification: | Ph.D |
Title: | Investigating CD28 co-stimulation in the control of human T cell activation |
Event: | University College London |
Open access status: | An open access version is available from UCL Discovery |
Language: | English |
Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
URI: | https://discovery.ucl.ac.uk/id/eprint/10141755 |




Archive Staff Only
![]() |
View Item |