Modulation of asymmetric cell division as a mechanism to boost CD8+ T cell memory
Cytotoxic T lymphocytes, when activated, generate progenies with different fates. Asymmetric cell division (ACD) is a mechanism that contributes to this process. A recent paper by the Oxenius group (IMB) identifies ACD being restricted to T cells endowed with "stemness" (i.e. naïve and memory cells that retain their ability to generate offspring with heterogeneous fates) and establishes interventions that increase ACD and consequently enhance divergent fate decisions.
Generation of diversity is a hallmark of immunity and implemented on different layers by adaptive immune cells. Asymmetric partitioning of fate-determinants is a mechanism that contributes to T cell differentiation and generation of progenies with different fates, such as short-lived effector cells and long-lived memory cells. However, it remains unclear whether the ability of T cells to divide asymmetrically is influenced by their differentiation state, as well as if enforcing asymmetric cell division rates would have an impact on T cell differentiation and memory formation. Using the murine infection model with lymphocytic choriomeningitis virus (LCMV), we established a correlation between cell stemness and the ability of CD8+ T cells to undergo asymmetric cell division (ACD). Specifically, naïve and memory CD8+ T cells, which retain stemness (i.e. the ability to generate offspring with heterogeneous fates), were able to undergo ACD, whereas terminally differentiated effector and exhausted T cells lacked the ability to undergo ACD. Transient inhibition of the mammalian target of rapamycin (mTOR), a key signaling pathway engaged after T cell activation, led to increased ACD rates in naïve and memory cells, and was able 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 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 opens new perspectives for vaccination and adoptive T cell transfer therapies.
Link to the paper in external page "Science Immunology".
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