Influence of Lck abundance on thymic selection, peripheral T cell activation and the formation of T cell memory
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Selection of the T cell repertoire in the thymus is governed by the need to create a repertoire of peripheral T cells that can respond to any foreign antigen in the context of self-major histocompatibility complex (MHC), while enforcing central tolerance to self-antigens. Perturbations in signalling molecules, that reduce the affinity of thymic selection, can lead to the production of a peripheral repertoire with increased autoimmunity, as has been shown for mutations in the Zap-70 kinase. Upstream of Zap-70 is Lck, the most proximal tyrosine kinase required for T cell receptor (TCR) triggering upon TCR engagement by peptide:MHC. In order to study how Lck influences T cell activation, a transgenic mouse model (LckVA), in which Lck is expressed constitutively from a T cell specific transgene and mice have very low expression of Lck (~5% of WT) in both the thymus and periphery, was used. It has been shown that Lck is critical for successful T cell development, yet the results of this thesis show that even 5% of WT levels of Lck are sufficient for selection of thymic T cells on both polyclonal and F5 TCR transgenic backgrounds. Previous studies utilising mice expressing an inducible Lck transgene, which also had reduced Lck expression in the periphery, showed Lck to be critical in determining the activation threshold of T cells. In contrast, peripheral T cells in LckVA mice had similar activation thresholds to wild type T cells, as measured by in vitro upregulation of early activation markers. Further analysis of LckVA peripheral T cells revealed differential influences of low expression of Lck on downstream signalling pathways upon TCR engagement. For example, ERK signalling was impaired, while calcium flux and proliferation were enhanced in LckVA T cells. Finally, LckVA T cells were altered in their ability to differentiate, showing enhanced production of cytokines and retaining the capacity to form memory cells.