Investigating the molecular mechanisms downstream of T cell receptor signalling during thymic T cell development

What prevents us from becoming reinfected with the same pathogen is the adaptive branch of the
immune system, which features T cells as key components. What distinguishes T cells from other
white blood cells is their T cell receptor (TCR), which bears specificity to a single antigen on the
surface of a pathogen. Upon encountering their cognate antigens, naive T cells become activated,
proliferate and differentiate into T cell subsets that are able to respond accordingly by releasing their
characteristic cytokines. This leads to inflammatory responses and pathogen elimination. Once
infection is cleared, T cells may remain as long-lasting memory T cells, capable of quick response to
possible reinfection with the same pathogen. Defects in the regulation and function of T cells may
result in a range of symptoms, from immunodeficient to autoimmune. Understanding how these cells
differentiate, are regulated and elicit their functions is essential to the development of effective
vaccination strategies and technologies in the pursuit of fighting disease.
TCR engagement activates a proximal network of signalling molecules, which contribute to nuclear
translocation of transcription factors that activate immediate early genes involved in T cell
proliferation, differentiation and response. Signalling branches according to the level of TCR
stimulation, as well as other stimuli such as cytokines, in order to generate the most appropriate T
cell response. The dynamics of transcriptional mechanisms following TCR signalling remain unclear,
as well as which particular pattern of stimulation leads to a particular T cell response.
This project will investigate how antigen recognition leads to T cells maturation in the thymus and how potentially self-reactive T cells are deleted. It will especially focus on how these processes are dynamically regulated, an aspect of T
cell immunology that remains largely unclear due to a lack of tools to study transcriptional dynamics.
This project will study the dynamics of T cell regulation and function, using a
novel transgenic technology to investigate the molecular mechanisms downstream TCR signalling
during T cell differentiation and response. The main objectives of this project are (I) to investigate
the dynamics of TCR stimulation during thymic selection processes, (II) to investigate the molecular
mechanisms of T cell differentiation following TCR engagement and (III) to determine how different T cell lineages differentiate in vivo following
antigen recognition.
We will use multidisciplinary approaches to address our aims and objectives. Thymic developmental
processes will be experimentally analysed by flow cytometry and RNA sequencing. These data will be
analysed by computational algorithms.
Through this project, we will be able to answer key questions in immunology, including how antigen
recognition lead to TCR signalling and thereby subsequently promote T cell deletion, maturation and
differentiation into distinct subsets, their phenotypical characteristics and, importantly, how these processes are
dynamically regulated over time. These combined approaches will improve on the current knowledge of T cell biology, will provide insights into how T cell response may be best modulated and will
identify potential molecular targets for bioengineering technologies.