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

Abstract

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.

The metabolic spectrum of memory T cells

“…Asymmetric cell division is initiated before the T cell begins to divide and results in the daughter cell distal to the antigen‐presenting cells having an increased propensity to develop a memory cell phenotype, whereas the daughter cell proximal to the antigen‐presenting cell is more likely to develop into a short‐lived effector cell During this process, asymmetry in mTORC1 and phosphinositide‐3 kinase activity, expression of cMYC and the amino acid transporter CD98 occurs . Furthermore, in human T cells, asymmetry in the daughter cells can be enhanced through transient inhibition of mTOR signaling . Collectively, these factors implicate metabolic reprogramming in addition to transcriptional programs and epigenetic regulation in determining the fate of activated T cells.…”

“…[36][37][38] Furthermore, in human T cells, asymmetry in the daughter cells can be enhanced through transient inhibition of mTOR signaling. 39 Collectively, these factors implicate metabolic reprogramming in addition to transcriptional programs and epigenetic regulation in determining the fate of activated T cells.…”

mTOR and other effector kinase signals that impact T cell function and activity

“…Nevertheless, mTOR is likely to play a role in this asymmetric cell division. By transiently inhibiting mTOR via rapamycin treatment, Borsa et al were able to increase asymmetric divisions and memory cell formation in ex vivo stimulated CD8 + T cells …”

Mapping bilayer thickness in the ER membrane

“…Not only are RITs present at the bud neck but also the thickening of the bilayer is on its own a key feature for their function in restricting lateral diffusion across the membrane. Adapting the tools developed here to animal cells may allow determining whether similar mechanisms drive the assembly and function of the lateral diffusion barriers observed in the ER and plasma membranes of metazoans [( 15 , 14 , 37 ); reviewed in ( 38 )] and provide insights into how ceramides influence processes such as asymmetric cell division [as observed in ( 39 )] and ciliogenesis ( 40 ). Furthermore, deciphering how the assembly and localization of the bud neck RITs is controlled will provide important insights into how cells assemble and regulate these structures.…”