Asymmetric cell division safeguards memory CD8 T cell development

The strength of T cell receptor (TCR) stimulation and asymmetric distribution of fate determinants are both implied to affect T cell differentiation. Here, we uncover asymmetric cell division (ACD) as a safeguard mechanism for memory CD8 T cell generation specifically upon strong TCR stimulation. Using live imaging approaches, we find that strong TCR stimulation induces elevated ACD rates, and subsequent single-cell-derived colonies comprise both effector and memory precursor cells. The abundance of memory precursor cells emerging from a single activated T cell positively correlates with first mitosis ACD. Accordingly, preventing ACD by inhibition of protein kinase Cζ (PKCζ) during the first mitosis upon strong TCR stimulation markedly curtails the formation of memory precursor cells. Conversely, no effect of ACD on fate commitment is observed upon weak TCR stimulation. Our data provide relevant mechanistic insights into the role of ACD for CD8 T cell fate regulation upon different activation conditions. [Display omitted] •Strong TCR stimulation promotes effector differentiation•Single colonies after strong stimulation comprise TE and TM following ACD•Inhibition of ACD strongly curtails memory formation on strong stimulation•ACD safeguards the generation of memory CD8 T cells on strong stimulation Memory potential of CD8 T cells decreases with increasing TCR signal strength. Gräbnitz et al. show that on strong TCR stimulation, ACD-derived single cells give rise to mixed-fate colonies, whereas SCD-derived single cells give rise to effector-fate colonies. Consequently, ACD functions as a safeguard for the generation of memory cells.