Cells constantly sense nutrient availability in their microenvironment, adapting function and survival to metabolic state. Driving this adaptation, mitochondria fine-tune their function in response to the dynamic metabolic requirements of the cell. Mitochondrial biogenesis is triggered to respond to higher metabolic needs while selective autophagy removes dysfunctional organelles. Changes in mitochondrial morphology couple location and shape of mitochondria to efficient energy production. Mitochondria fuse and divide forming interconnected networks of filamentous organelles in the cell or isolated fragmented units. Furthermore, mitochondria are central signaling hubs computing complex signaling networks and communicating with the nucleus. This extraordinary mitochondrial plasticity is critical to T cells, which constantly surveil their environment, patrolling tissues and trafficking to and from lymphoid organs. T cells coordinate multiple aspects of adaptive immunity throughout life including responses to pathogens, allergens and tumours. While doing so, T cells modulate metabolism depending on antigen-driven and microenvironmental signals. In recent years, the emerging field of immunometabolism started to unveil the role metabolism in shaping the immune function and how modulating cell or organismal metabolism affects immune cell differentiation and properties.
Our research: T cell cytotoxic and memory features are key for T cells to fight more efficiently infections or cancer and protecting 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 in immunity, inflammation and aging.
Our goals: In our lab we aim at further investigating the molecular and environmental cues regulating metabolic programs in T cells during an immune response against pathogens and cancer and in autoimmune diseases. Our long-term goal is to establish a comprehensive understanding of the biology of cardiolipin plasticity in health and disease, opening up unique opportunities for therapeutic interventions in many conditions in which CL is altered ranging from Barth syndrome to neurodegeneration and traumatic brain injury, from multiple sclerosis to heart failure. Moreover, understanding the regulatory circuit behind cardiolipin synthesis may reveal new strategies to increase CL and counteract aging dependent decline in mitochondrial function and improve healthspan.
Our successes: We have discovered that cardiolipin pool and profile are modulated by intrinsic and microenvironmental stimuli in CD8+ T cells and that CD8-mediated adaptive immune responses are impaired when cardiolipin synthesis and remodeling are deficient. This work shows that the dynamic nature of cardiolipin drives T cell activation, differentiation, and adaptations to microenvironment. Indeed, cardiolipin synthesis allows T cell survival and adaptation in culture settings (like glucose restriction or specific cytokine and co-receptor stimulations) that invoke higher spare respiratory capacity (SRC), a measure of a cell’s ability to make extra ATP from OXPHOS upon increased energy demand. Moreover, T cells deficient in the cardiolipin-synthesizing enzyme PTPMT1 respond poorly to infections and fail to develop memory T cells. Conversely, increasing CL content in T cells improves their long-term survival and memory potential.
Our methods/techniques: We use a multidisciplinary approach that combines 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. Our methods also include molecular and biochemistry techniques to characterize and manipulate signaling and metabolic pathways during T cell activation and differentiation.