Dr Mariana Borsa; University of Oxford
Mariana's first steps as an immunologist started in Brazil while studying antimicrobial responses in shrimps and oysters during her BSc. studies (2005-2010), for which she was awarded the University Medal. She then dedicated her MSc. studies (2010-2012) to understand how the unfolded protein response in lymphocytes and monocytes is impacted by HIV infection and antiretroviral therapies. Close to completing her studies in the Federal University of Santa Catarina (UFSC), she got a permanent position as a lecturer in the same institution, where she taught Biology for 3 years. To pursue a career as a scientist she moved to Switzerland, where she did her PhD in Immunology at ETHZ (2014-2018), under the supervision of Prof. Annette Oxenius. There Mariana was very successful in bringing new insights into how asymmetric cell division, a conserved mechanism to generate diversity, impacts T cell fate as a requirement for the establishment of memory. She was the first to describe that effector and terminally exhausted CD8+ T cells lose their ability to undergo asymmetric mitoses, showing that asymmetric cell division is a feature of cells that retain stemness. She also developed a strategy to boost asymmetric cell division in CD8+ T cells by transient inhibition of mTOR, which proved to be highly efficient to benefit memory formation – a potential new translational strategy to improve immune responses, especially in the context of chronic infections, tumours and ageing. For her PhD work, she was awarded the prestigious ETH Silver Medal. She is currently a senior postdoctoral fellow at the University of Oxford, under the mentorship of Prof. Katja Simon and Prof. Mike Dustin, where she has been investigating the role of autophagy in the balance between stemness and differentiation. In the context of haematopoiesis, she has recently shown that autophagy is needed to restrain mTORC1-mediated cellular anabolism in HSCs. Her current efforts focus on understanding how organelle ageing regulates T cell metabolism and fate decision. To develop this work, she was awarded fellowships from the Swiss National Science Foundation, Marie Skłodowska-Curie Actions and Wellcome Trust.
T cell immunity is impaired during ageing, particularly in memory responses needed for efficient vaccination. Autophagy and asymmetric cell division (ACD) are cell biological mechanisms key to memory formation, which undergo a decline upon ageing. Thus, we aimed to decipher whether autophagy regulates the early-rise of asymmetric T cell fates and investigate whether there is a causal link between ACD and in vivo T cell fate decisions, as evidence has remained highly correlative. Our results are consistent with the concept that initiation of asymmetric T cell fates is indeed regulated by autophagy. Firstly, by analysing the proteome of first-daughter CD8+ T cells following TCRtriggered activation, we observed that mitochondrial proteins rely on autophagy for their asymmetric inheritance and that damaged mitochondria are polarized upon first division. These results led us to evaluate the functional impact of unequal inheritance of different mitochondrial populations on T cell function. To achieve that, we used a novel mouse model that allows sequential tagging of mitochondria in mother and daughter cells, enabling their isolation and subsequent in vivo analysis of CD8+ T cell progenies based on a pre-mitotic cell cargo. Autophagy-deficient CD8+ T cells showed impaired clearance and symmetric inheritance of old mitochondria, suggesting that both segregation and degradation events promote asymmetry and are needed to generate T cells devoid of old organelles. Daughter cells inheriting old mitochondria are more proliferative, glycolytic and show poor survival in absence of TCR stimulation. Adoptive transfer of cells followed by antigen-specific infection revealed that progenies inheriting old organelles have reduced memory potential, whereas daughter cells that have not inherited old mitochondria from the mother cell are long-lived, able to re-expand upon cognate-antigen challenge and produce effector cytokines upon re-stimulation. Proteomic and single-cell transcriptomic analysis of cells inheriting aged mitochondria suggest that their early fate divergence relies on one carbon metabolism as a consequence of poor mitochondrial quality and function. These findings increase our understanding of how T cell diversity is early-imprinted and will help foster the development of strategies to modulate T cell function, which is particularly relevant in the context of immune rejuvenation and regenerative medicine.
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