Corrado, Mauro - CAP 21

How T lymphocytes establish long-term immune memory  (Figure1) has been attributed to multiple mechanisms involving prolonged cellular longevity, post-translational regulation of key proteins, and epigenetic reprogramming of the cellular transcriptome.

In recent years, the emerging field of immunometabolism has started to unveil the role of metabolism in shaping immune function, and to reveal how modulating cell or organismal metabolism can affect immune cell differentiation. In my group at CECAD Research Center we aim at investigating how mitochondrial function is regulated in T cells in health and disease and how its dysregulation during ageing or pathology results in impaired or altered immune response. Our long-term goal is to clarify the transcriptional and microenvironmental mechanisms involved in the development of long-term immune memory and define how metabolic plasticity modulates cellular responses to stress and immune challenges.

The research in my group focuses on the role of mitochondrial metabolism, and in particular of cardiolipin (the distinctive inner mitochondrial membrane phospholipid), in shaping immunity, inflammation, and ageing. The importance of cardiolipin in mitochondrial function is evidenced not just by the X-linked inherited pathology Barth syndrome, a result of cardiolipin remodeling deficiency but also by its role in many conditions ranging from neurodegeneration to traumatic brain injury, from multiple sclerosis to heart failure. Yet we understand little about how CL alterations cause, participate or exacerbate these conditions beyond regulating OXPHOS efficiency.
We have showed how the dynamic synthesis and remodeling of cardiolipin is responsible for the metabolic and functional plasticity of CD8+ T cells during an immune response (Figure 2-3) (Corrado et al., 2020).

Our research also highlights CD8+ lymphopenia and functional impairments as previously uncharacterized features of Barth syndrome, where patients have Tafazzin mutations and so defective cardiolipin remodeling. Moreover, our recent work on the metabolic regulation of thymic development has shown how metabolism influences the immune system starting from the developmental stage (Corrado et al., 2021). This is important because one of the first manifestations of ageing is thymic involution. Our work shows how mitochondrial respiration impairment has long-lasting consequences on immune function and immune memory development.

In our lab, we aim at better understanding how metabolism impacts immune function in ageing, cancer or infections. The acquired knowledge about basic metabolic and signaling circuits in T cells in these conditions will lead us to harness those same pathways to improve disease prevention, treatment and outcome. Thus, our approach on immunometabolism reveals an extraordinary translational potential. In particular, our research plan has clear clinical relevance in the following three directions:

• Patients affected by mitochondrial diseases (MDs) also show immune defects linking systemic metabolism to immune function alteration (Corrado and Pearce, 2022). Up to half of the patients with MDs experience recurrent or severe upper respiratory tract infections, often resulting in life-threatening conditions. This percentage increases to almost 90% of pediatric MD patients. We have a specific interest in defining the immune and inflammatory landscape of patients affected by Barth Syndrome, characterized by mutations in the acyltransferase Tafazzin responsible for the process of cardiolipin remodeling.

• Establishing long-term immune memory able to recognize and fight previously encountered antigens is central to the success of any vaccination campaigns or cancer immunotherapy. Nevertheless, the mechanisms underlying induction and maintenance of immunological memory still remain elusive. Our line of research aims at identifying and characterize metabolic checkpoint to be exploited in cancer immunotherapy or to improve current and future vaccine regimens.

• Mitochondria are central hub for inflammatory signals with (among other mechanisms) the release of mitochondrial DNA – mtDNA – to the cytoplasm or the relocalization of cardiolipin to the outer mitochondrial membrane resulting in the activation of strong pro-inflammatory cascades culminating in the expression of Type I Interferons and IL-1β (Figure 4). In our lab, multiple projects aim at defining in vivo the contribution of mitochondrial defects to inflammation.

Overall, these observations show the functional nuances of metabolism in T cell immunity suggesting that modulation of cellular or organismal metabolism influence directly immune function. They also imply a possible partially immunocompromised condition in patients affected by mitochondrial diseases (both in terms of immune response to pathogens and vaccines) and open important questions:

• How does mitochondrial fitness regulate T cell differentiation and function?
• Which metabolic and signaling rewiring mechanisms are driven by mitochondrial deficiencies in T cells?
• How do mitochondrial deficiencies modulate inflammation?

Starting from these questions, our research program to further delve into T cell biology and physiology when mitochondrial metabolism is altered.

For more information about Dr. Corrado`s work, please check this site.