Unlock T cell diversity: Asymmetric cell division and autophagy as keys to human T cell responses to vaccination 9338

Description Vaccine effectiveness is intricately tied to the formation of stem-like memory T cells. We aimed to elucidate whether vaccine responses hinge on known cellular processes to preserve T cell diversity by promoting the generation of stem cells: asymmetric cell division (ACD) and autophagy. ACD enables T cells to generate progenies inheriting divergent fates upon antigen encounter through the unequal inheritance of cell cargoes, while autophagy is a recycling mechanism that restrains the accumulation of cellular damage. Both mechanisms decline with age, potentially explaining poor memory responses in older adults. We are the first to show that mitotic human CD8 T cells asymmetrically segregate components of the autophagic machinery (e.g. autophagosomes, lysosomes and p62). By isolating progenies emerging from ACD and performing proliferation and survival functional assays, we could link ACD to fate divergence. We also found that autophagy flux and expression of TFEB, a transcriptional regulator of autophagy and lysosomal biogenesis, are linked to cell fate commitment in the context of antigen-specific CD8 T cell responses from an influenza vaccine trial. Remarkably, an individual’s ACD potential positively correlated with their responsiveness to the vaccine. We are currently developing gene editing and pharmacological tools to modulate TFEB and autophagy, aiming to promote ACD, which would benefit rejuvenating T cell responses in the context of ageing and regenerative medicine.