TY  - GEN
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/24501/
Y1  - 2018///
TI  - Quantifying CD8+ T cell dynamics in infectious diseases
N2  - CD8+ T cells are an important part of the adaptive immune system. They are not only able to efficiently kill infected cells, but can also provide protection against subsequent infections.
Recently, T cell-based vaccines, which are able to elicit protection-mediating CD8+ T cell responses, have shown their potential against various infectious diseases, including malaria or HIV.
However, the efficient implementation of these approaches is currently hampered by a lack of knowledge regarding the dynamical processes generating the protective responses. In this thesis, we combined experimental data and mathematical modelling to analyse and quantify CD8+ T
cell dynamics in different infectious diseases.
First, we study a specific immune responses elicited by cytomegalovirus (CMV) infection, known as 'memory in
ation'. We used mathematical modelling to test different hypotheses regarding the processes that generate and maintain memory in ation and analysed how viral
dynamics shape the corresponding CD8+ T cell responses. Since CMV has already been used as a vaccine vector expressing foreign epitopes, our findings are relevant for improving the efficacy of these vector-based vaccination approaches.
To generate sufficient protection, vaccination strategies usually require the application of one or more booster injections. Here, factors such as dosage, frequency and timing of injections can influence the protective levels reached. To determine the impact of current vaccination
strategies against malaria, we analysed the in
uence of vaccination regimens, differing in dosage
and frequency of injections, on the generation of organ-specific CD8+ T cell responses. We identified the underlying cellular differentiation and migration pathway and determined the impact of different vaccination doses on the build-up and maintenance of protection-mediating
liver-resident memory cells. Our results do not only provide a quantitative understanding of CD8+ T cell responses elicited by immunisation, but can also be used to improve existing vaccination approaches.
Understanding the impact of T cell-based vaccination regimes on the immune system requires knowledge about the underlying cellular dynamics. While mathematical modelling allows the
determination of differentiation pathways and the quantification of cellular turnover, the reliability
of these analyses depends strongly on the quality of the available data. While the labelling of cells has been a useful method to increase the amount of information within cellular data, it has not been analysed so far how the design of applied labelling strategies aspects the mathematical estimation of cellular turnover. To this end, we determined the robustness of different labelling
strategies to infer cellular dynamics including data suffering from experimental limitations. Our
fndings can be used as a guideline to determine cellular dynamics more accurately in future experiments.
In summary, by combining experimental data and mathematical modelling our results do not provide a quantitative understanding of CD8+ T cell responses in infectious diseases, but can also be used to improve the efficiency and efficacy of T cell-based vaccines.
A1  - Gabel, Michael
AV  - public
ID  - heidok24501
ER  -