McIntyre, Andrew;
(2024)
The role of CD4+ help in promoting CD8+ T cell
function following allogeneic haematopoietic
stem cell transplantation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Following allogeneic haematopoietic stem cell transplantation (alloHSCT), CD4+ T cells are the slowest major immune population to reconstitute. An extended lymphopenia leads to deficiencies in the recovery of immune fitness and of protective mechanisms against infected and malignant cells. The CD8+ T cell compartment reconstitutes in the absence of CD4+ T cell help and is characterised by features of dysfunction and terminal differentiation. The multicentre, randomised phase II clinical trial PROT4 (NCT01240525) compared the outcomes of alloHSCT patients receiving the early adoptive transfer of a donor CD4+ T cell-enriched infusion product, versus a control group receiving no infusion. In my PhD, I analysed the impact of the infusion on the reconstitution of lymphocyte populations, in particular the recovering T cell compartment. CD4+ T cell infusion decreased the rate of T cell reconstitution owing to a reduced expansion of CD8+ T cells in the year following alloHSCT. When examined at high resolution using multiparametric flow cytometry and single cell transcriptional profiling, this was revealed to be due to a reduction in the accumulation of clonally restricted and terminally differentiated CD8+ effector T cells (CD8+ TTE). In the CD4+ T cell compartment, the infusion sustained the presence of a circulating T follicular helper cell (CD4+ cTFH) phenotype, and this population negatively correlated with the CD8+ TTE cells. An in vitro model of CD8+ T cell progressive differentiation was developed to test the impact of CD4+ TFH-like cells on the loss of potential in CD8+ T cells. CD4+ TFH-like cell help improved memory potential in the CD8+ T cell pool following secondary stimulation in a partially IL- 21-dependent manner. As such, CD4+ TFH-like cells are a potential candidate cell population to enrich in future infusion products to aid T cell recovery following alloHSCT.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The role of CD4+ help in promoting CD8+ T cell function following allogeneic haematopoietic stem cell transplantation |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10188958 |
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