DamAged memories: organelle heterogeneity en route to T cell diversity

Maintenance of long-lived and quiescent stem cells is impaired during ageing, which negatively impacts tissue regeneration by restricting cell diversity. In the context of T lymphocytes, ageing is linked to profound changes in their repertoire, which becomes less diverse due to naïve T cell attrition. This leads to the accumulation of terminally differentiated cells and results in poorer immune responses. I aim to understand whether T cell diversification is fostered by the unequal inheritance of heterogeneous pools of organelles with distinct chronological ages. I will focus on mitochondria and peroxisomes, as T cell metabolism is key to cell fate decisions. I hypothesize that i) organelle inheritance is influenced by early events following T cell activation, ii) organelle ageing leads to changes in trafficking and function and iii) the organelle repertoire can be manipulated to rejuvenate ageing T cells. To test these hypotheses, we will: (1) Investigate whether unequal inheritance of aged vs. young organelles is determined by pre-mitotic events and the consequences of perturbing organelle trafficking; (2) Dissect whether the role of organelle fission in regulating mitochondrial and peroxisomal dynamics discriminates organelles by age; (3) Develop tools to rejuvenate cells that accumulate damage and dysfunctional cargo by targeting organelle inheritance. All aims will address the potential reciprocal relationship between organismal ageing and organelle ageing as drivers of impaired T cell stemness. The focus on ageing relies on the potential to use any discovered modulation strategies in T cell therapies, being older adults particularly vulnerable to pathologies linked to immune and metabolic disorders. These findings will also have impact beyond the field of immunology, as organelle ageing is a general cell biological phenomenon and relevant across different stem-like cell types, which can have broader implications in the perspective of tissue regeneration.