Asymmetric cell division and autophagy are key to human CD8 T cell responses during vaccination

Thesis

Vaccine-induced protection relies on the generation of stem-like memory T cells, a process sustained by two conserved, organelle-centric mechanisms: asymmetric cell division (ACD) and autophagy. ACD enables T cells to produce progenies with divergent metabolic and functional fates upon antigen encounter through the unequal inheritance of cellular cargo, while autophagy provides essential metabolic substrates to meet energy demands and mitigate cellular stress. Both mechanisms decline with age, potentially explaining the diminished memory responses observed in older adults. These processes regulate T cell diversity and fate by maintaining memory T cell progeny, yet how they intersect in human immunity remains largely unexplored.

In this thesis, I show for the first time that mitotic human CD8+ T cells give rise to daughter cells with distinct transcriptional and functional phenotypes. These divergent fates are coupled to the asymmetric segregation of autophagy-related organelles, including autophagosomes and lysosomes, resulting in unequal autophagic flux during the differentiation of daughter cell. Extending these findings to an influenza vaccine trial, I demonstrate that autophagic flux dynamically tracks with the clonal expansion and contraction of antigen-specific T cells, alongside changes in the autophagy master regulator TFEB and the metabolic marker GLUT1. Notably, individuals with stronger vaccine responses exhibited higher levels of ACD and greater asymmetric inheritance of autophagosomes, linking early cellular segregation and degradation events to long-term immune fitness in humans. Furthermore, transient inhibition of mTORC1 with rapamycin enhanced ACD levels, resulting in better memory T cell survival. Together, these findings identify ACD and the asymmetric inheritance of autophagy machinery as pivotal regulators of human adaptive immunity and as potential therapeutic targets to improve vaccine efficacy.

Authors: Luo, L

• DOI: 10.5287/ora-5rv6rj7vb
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: vaccine response; autophagy; asymmetric cell division; human T cell
• Subjects: Immunology