Use this URL to cite or link to this record in EThOS:
Title: Quantification of T lymphocyte dynamics in vivo
Author: Costa del Amo, Pedro
ISNI:       0000 0004 8504 4546
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
Availability of Full Text:
Access from EThOS:
Access from Institution:
Despite the significant contributions of theoretical immunology to our understanding of the dynamic mechanisms regulating adaptive immunity, there are still many fundamental processes which need to be comprehended from a quantitative perspective (e.g. the generation and maintenance of T cell memory, the regulation of homeostasis, etc.). Mathematical models have become indispensable to handle the interpretation of the complex quantitative data generated by the recently developed experimental techniques to study lymphocyte dynamics. However, all models are at best simplified descriptions of the system under study, and the accuracy of their predictions and estimations is always determined by the veracity of their biological assumptions. The first objective of this thesis is the evaluation of the validity of the commonly assumed age-independence of lymphocyte fate in mathematical models in immunology. A series of recent, high-profile studies from the Hodgkin group show that lymphocyte fate (division, death, differentiation) is dependent on the age of the cell, at least in murine cells in vitro. However, the rules of T cell fate in humans in vivo are unknown. We found that the age-independent model provides the best description of human naïve and memory CD4+ and CD8+ T cell turnover in heavy water labelling experiments, and that the age-dependent model from the Hodgkin group fails to describe the link between lymphocyte division and death which is explored combining Annexin V staining and deuterated glucose labelling. The second objective is the quantification of the dynamics of the recently identified stem memory T cell subset in humans in vivo, with a strong focus on their contribution to the generation and the maintenance of T cell memory. Using a multidisciplinary approach combining mathematical modeling, and heavy water labeling, Ki67, and telomere length data, we show: i) that the TSCM population is kinetically heterogeneous (i.e. it is formed by different subpopulation with different average turnover rates); ii) that the TSCM population is maintained in a state of dynamic flux with considerably high replenishment rates; and iii) that TSCM dynamics are compatible with the increasingly believed hypothesis that the TSCM population could be the main T cell precursor responsible for the maintenance of T cell memory.
Supervisor: Asquith, Becca Sponsor: European Union
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral