| Abstract |
Successful immune responses rely on diversity. Being equipped with highly variable T cell receptors (TCRs), which convey antigen specificity, CD8+ T cells exhibit an immense repertoire of different naïve cells even before antigen encounter, but for an immune response to be effective, both clonal expansion, and differentiation must take place. Upon cognate antigen activation, one single naïve CD8+ T cell can give rise to different progenies, including effector and memory cells. How this diversity is generated, is still a phenomenon incompletely elucidated, but some mechanisms were reported to be involved in fate determination, such as differential strength of TCR activation, and differential exposure to inflammatory stimuli, leading to differential transcriptional and metabolic profiles, epigenetic control of gene expression, and asymmetric cell division (ACD). Concerning ACD as a means to foster diversification, most studies were limited to describe the mitotic polarization of a variety of components in activated naïve T lymphocytes, leading to the rise of two daughter cells inheriting distinct potential fates. We set out to study whether the ability to undergo ACD is limited to certain CD8+ T cell subsets and developed a strategy to modulate ACD rates. Using the murine Lymphocytic Choriomeningitis virus (LCMV) infection model, we established a correlation between ACD and cellular stemness, as naïve and memory CD8+ T cells (which exhibit stemness in terms of self-maintenance and being able to generate progenies with different fates) were found to divide asymmetrically, while terminally differentiated cells, as short-lived effector and exhausted cells, lacked this ability. ACD modulation was achieved by transient mTOR inhibition, leading to higher ACD rates in naïve and memory cells, and reestablishment of ACD in pre-terminally exhausted PD-1int CD8+ T cells. The ability to undergo ACD correlated with memory potential. Upon adoptive transfer, progenies of mTOR-inhibited LCMV-specific TCR transgenic P14 cells, ...
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