Asymmetric cell division safeguards memory CD8 T cell development

Abstract

The strength of T cell receptor (TCR) stimulation and asymmetric distribution of fate determinants are both implied to affect T cell differentiation. Here, we uncovered asymmetric cell division (ACD) as a safeguard mechanism for memory CD8 T cell generation specifically upon strong TCR stimulation. Using live imaging approaches, we found that strong TCR stimulation induced elevated ACD rates and subsequent single cell derived colonies comprised both effector and memory precursor cells. The abundance of memory precursor cells emerging from a single activated T cell positively correlated with first mitosis ACD. Accordingly, preventing ACD by inhibition of PKCzeta during the first mitosis upon strong TCR stimulation markedly curtailed the formation of memory precursor cells. Conversely, no effect of ACD on fate commitment was observed upon weak TCR stimulation. Our data provide new mechanistic insights into the role of ACD for CD8 T cell fate regulation upon different activation conditions.

Inheritance of old mitochondria controls early CD8+T cell fate commitment and is regulated by autophagy

“…By using sorted populations or approaches that provide single-cell resolution, we determined that the metabolism, survival and proliferative capacity of these progenies is different. Exhibiting lower translation rates, higher frequencies of slow-dividing cells and CD62L expression and better survival capacity in absence of antigen, MitoSnap-cells clearly showed a stronger memory phenotype than MitoSnap+ cells 22,38 .…”

“…Effector CD8 + T cells are highly proliferative, while memory CD8 + T cells divide slower and are more quiescent. This is a feature that is established early on following T cell activation, with cell cycle speed predictive of CD8 + T cell fate 22,38 . CD8 + T cells with different clonal expansion rates have different metabolic demands, effector cells being more reliant on glycolysis, while long-lived naïve and memory cells mostly perform mitochondrial oxidative phosphorylation and fatty acid oxidation to produce ATP 32,33 .…”

“…4F). Interestingly, autophagy-sufficient remaining surviving cells exhibited distinct phenotypes, being CD44 + CD62L + cells, an expression pattern seen quiescent memory cells 22,38 , more abundant amongst MitoSnap-progenies (Fig. 4G).…”

“…S1B). As it has been described that IS formation and TCRaffinity and signalling strength are crucial for asymmetric T cell division [21][22][23] , we excluded that any differences in T cell activation due to loss of Atg7 interferes with ACD readouts by using an inducible model of autophagy deletion (Atg16l1 fl/fl Ert2 Cre ). Here activation happens with functional autophagy, as Atg16l1 is deleted only upon in vitro Z-4-Hydroxytamoxifen (4OHT) treatment (Fig.…”

“…Here we address this question using CD8 + T cells. ACD in CD8 + T cells is important for the generation of two distinct cell types, through the early generation of effector-like and memory-like daughter cells 21 that occurs from the first mitosis after naïve T cell activation by high-affinity TCR stimulation 22,23 . The daughter cells emerging from ACD inherit several layers of asymmetry, including the differential expression of surface markers, transcription factors, divergent metabolic activity and translation [24][25][26][27] .…”