AbstractThe aim of this project was to study the role of TRAF6 and TRAF6-mediated signals in immune cells. Initially this project focused on characterising the phenotype of a TRAF6 mutant mouse model in which an E3 ligase inactive mutant of TRAF6 was knocked in to all cells of the body (TRAF6[L74H]). Mice lacking TRAF6 E3 ligase activity were shown to develop a severe inflammatory autoimmune phenotype, characterised by systemic organ inflammation, elevated serum titres of immunoglobulins, autoantibodies and dysregulation of the peripheral T cell populations. While thymic T cell populations were comparable to wildtype, peripheral T cell populations were dysregulated, with increased numbers of T follicular helper cells, T regulatory cells and CD8+ T cells observed. These data therefore highlight an important role for TRAF6 E3 ligase activity in immune homoeostasis.
The second part of this thesis examined how cytokines that activate TRAF6 control CD8+ T cell function. Using CD8+ cytotoxic T cells as a model system, we observed that the IL1 family cytokines IL18 and IL33 modulate CTL metabolism. Acting in combination with IL12, which induces IL1 family receptors, we observed that IL18 and IL33 induce a short-lived acute metabolic response. Characterisation of this response using high resolution mass spectrometry revealed that IL18 and IL33 controlled core metabolic proteins including translational machinery such as the EIF complex, as well as a repertoire of essential nutrient transporters including those responsible for the uptake of Glucose. We further show that underlying this ability of IL18 and IL33 to control CTL metabolism is their ability to sustain expression of key nodes in CTL metabolism such as the transcription factor Myc and activity of mTORC1. Taken together, these results highlight how alarmins control CD8+ effector T cells as part of the immune systems response to infection or damage.
|Date of Award
|Doreen Cantrell (Supervisor) & Philip Cohen (Supervisor)