1. Research Background:
The adaptive immune system consists of a humoral branch, represented by B cells and antibodies, and a cellular branch, involving T cells that maintain homeostasis in tissues by controlling acute and chronic infections, surveilling for cancer cells, and maintaining proper immunoregulation. CD4 and CD8 T cells have different functions with CD4 mainly instructing other cells of the immune system regarding the type of immune response to mount and CD8 T cells having more direct function in targeting infected cells. Upon infection naïve T cells undergo clonal expansion to generate effector T cells (TEFF) able to directly kill infected cells or cancer cells. When the latter have been eliminated, most of TEFF die with some cells differentiating into memory T cells (TMEM) allowing for long term protection against the same pathogen (or cancer). Dysregulation of TMEM cell development may result on one side in impaired immunological memory formation, on the other in the development of autoimmunity or inflammation. The dynamic nature of T cells is also mirrored by their dynamic metabolism. T cells sense the nutrient and cytokine microenvironment composition and respond to activation and differentiation stimuli by modulating their metabolism. TEFF cells are highly metabolically active exploiting high levels of glycolysis for biosynthetic needs. TMEM cells are more quiescent and rely on oxidative phosphorylation for their survival and energetic requirements. So mitochondrial function and integrity are central in shaping an efficient immune response.
2. Research questions addresses by the group:
T cell cytotoxic and memory features are key for T cells to fight more efficiently infections or cancer and protect us from their reoccurrence via long-lasting immune memory. Conversely, T cell function needs to be shut down in the context of autoimmune diseases to reduce disease severity. Research in Corrado lab is focused on better understanding the metabolism of T cells during an immune response and how metabolism can be harnessed to modulate T cell function. To do so, we study the role of cardiolipin – the main phospholipid of the inner mitochondrial membrane - its synthesis and remodeling and how they are regulated in in vivo models of T cell immunity. Moreover, we investigate how immune cell functional decline during ageing and contribute to a general inflammatory state defined inflammageing and which might be the strategies to counteract this process and improve healthspan and immune function during ageing.
3. Possible projects:
We offer multi-disciplinary projects that combine classic immunology experiments to study in vivo T cell immunity in transgenic mouse models in the context of infection, cancer and autoimmunity and integrate them with state-of-the-art metabolomic and lipidomic approaches to characterize their metabolism and function. To examine the role of cardiolipin synthesis and remodeling deficiency in different tissues we have generated mouse models where Ptpmt1, responsible for cardiolipin synthesis, and Taz, responsible for cardiolipin remodeling, are ablated in immune cells or other tissues. These mouse lines will allow the analysis of the consequences of cardiolipin profile alteration in immunity and ageing.
4. Applied Methods and model organisms:
We use genetic mouse models to study the mechanisms regulating immunity, tissue homeostasis and inflammation in vivo. In our lab, we combine in vivo mouse phenotyping with in vitro biochemical, genome editing techniques and quantitative proteomics and metabolomics by mass spectroscopy.
5. Desirable skills and qualifications:
We are seeking a highly motivated PhD candidate to join our team investigating the role of metabolism in shaping the immune response. Applicants should have a solid background in cell biology, biochemistry and immunology. Experience in mouse experimentation would be advantageous but is not a prerequisite.
- Corrado M, et al. (2020) Dynamic cardiolipin synthesis is required for CD8+ T cell Immunity, Cell metabolism. 32, 981-995.
- Zhang J., et al. (2011) Mitochondrial Phosphatase PTPMT1 is essential for caridolipin biosynthesis. Cell Metabolism. 13, 690-700.
- Acehan D, et al. (2011) Cardiolipin affects the supramolecular organization of ATP synthase in mitochondria. Biophys J, 100(9): 2184–2192
- Pearce E.L. & Pearce E.J. (2013) Metabolic Pathways in Immune Cell Activation and Quiescence. Immunity. 38: 633-43
- Buck M.D., et al. (2016) Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming. Cell, 166(1): 63–76