SPArKLE · New players in immunometabolism: investigating the role of succinate and pyruvate kinase in T cell immunity

New players in immunometabolism: investigating the role of succinate and pyruvate kinase in T cell immunity

During its 16-month duration, the SPArKLE training programme provided an experienced researcher (ER) with expertise in immunology with a high-quality training in the field of immunometabolism. This field represents an emerging frontier in immunological research, and over the past 15 years it revolutionised our view on how the immune system works. It is indeed now clear that immune cells regulate the generation and strength of immune responses by fine-tuning their intracellular metabolic profile, and that alteration of metabolic pathways in specific immune cell subsets can impair their activation, polarisation and fate. In particular, a large body of evidence indicate that intracellular metabolism controls the activation and inflammatory potential of CD4+ T cells. This immune cell population is essential for pathogen clearance and long-term immunity, for example after vaccination. On the other hand, over-activation of CD4+ T cells may be harmful for the body, leading to uncontrolled systemic and local inflammation, and causing the development of immune-related pathologies such as autoimmune and allergic diseases, which have a huge socio-economic impact on national and international health agencies. Of note, the inflammatory activity of CD4+ T cells represents a major target of many disease-modifying drugs used for the treatment of such pathologies. It is therefore evident that a better understanding of the biological processes regulating CD4+ T cell functions would lead to the development of novel therapeutics specifically affecting T cell activation and detrimental activity. Given the increasing incidence of immune-related disorders worldwide, these new therapeutic approaches would have a major impact on the global community. During the SPArKLE project, the ER investigated the role of the metabolite succinate and the enzyme pyruvate kinase (PK) in CD4+ T cells. Previous reports showed that succinate and PK play an important role in the functionality of certain immune cell subsets and in the development of inflammatory pathologies, but no studies have specifically evaluated if such molecules regulate CD4+ T cell activation and pathogenicity. Therefore, the overall aim of the SPArKLE research programme was to evaluate whether succinate and PK play a role in the activation, polarisation and functionality of murine and human CD4+ T cells, with the final goal to identify novel potential targets with therapeutic utility in inflammatory and autoimmune pathologies. The results obtained during the development of the SPArKLE project indicate that while succinate plays a minor role in the functionality of CD4+ T lymphocytes, modulation of the activity of the enzyme PK, in particular of its isoform PKM2, could limit CD4+ T cell pro-inflammatory activity and the development of autoimmunity. The project thus identified PKM2 as a potential therapeutic target for the treatment of T cell-mediated inflammatory diseases.

Data: CORDIS, © European Union