Modulation of asymmetric cell division as a mechanism to boost CD8+ T cell memory

Abstract

CD8+ T cell memory potential can be improved by enforcement of asymmetric cell division. RAPping their way to stemness One interesting property of stem cells is their ability to undergo asymmetric cell division (ACD), which allows one of the daughter cells to retain stemness, whereas the other daughter cell becomes more differentiated. Akin to stem cells, memory cells in the immune system including memory T cells have the ability to undergo ACD. Borsa et al. have developed a strategy to enhance the ability of memory T cells to undergo ACD. They show that transient inhibition of the mTOR pathway using rapamycin enhances the memory potential of CD8+ T cells and their ability to undergo ACD. Developing methods to enhance T cell memory remains critical on several fronts, from vaccination to T cell–centric immunotherapies. Asymmetric partitioning of fate determinants is a mechanism that contributes to T cell differentiation. However, it remains unclear whether the ability of T cells to divide asymmetrically is influenced by their differentiation state, as well as whether enforcing asymmetric cell division (ACD) rates would have an impact on T cell differentiation and memory formation. Using the murine LCMV infection model, we established a correlation between cell stemness and the ability of CD8+ T cells to undergo ACD. Transient mTOR inhibition was proven to increase ACD rates in naïve and memory cells and to install this ability in exhausted CD8+ T cells. Functionally, enforced ACD correlated with increased memory potential, leading to more efficient recall response and viral control upon acute or chronic LCMV infection. Moreover, transient mTOR inhibition also increased ACD rates in human CD8+ T cells. Transcriptional profiling revealed that progenies emerging from enforced ACD exhibited more pronounced early memory signatures, which functionally endowed these cells with better survival in the absence of antigen exposure and more robust homing to secondary lymphoid organs, providing critical access to survival niches. Our data provide important insights into how ACD can improve long-term survival and function of T cells and open new perspectives for vaccination and adoptive T cell transfer therapies.