Regulation of Asymmetric Division and CD8+ T Lymphocyte Fate Specification by Protein Kinase Cζ and Protein Kinase Cλ/ι

Abstract

During an immune response against a microbial pathogen, activated naïve T lymphocytes give rise to effector cells that provide acute host defense and memory cells that provide long-lived immunity. It has been shown that T lymphocytes can undergo asymmetric division, enabling the daughter cells to inherit unequal amounts of fate-determining proteins and thereby acquire distinct fates from their inception. Here, we show that the absence of the atypical protein kinase C (aPKC) isoforms, PKCζ and PKCλ/ι, disrupts asymmetric CD8+ T lymphocyte division. These alterations were associated with aberrant acquisition of a ‘pre-effector’ transcriptional program, detected by single-cell gene expression analyses, in lymphocytes that had undergone their first division in vivo and enhanced differentiation toward effector fates at the expense of memory fates. Together, these results demonstrate a role for aPKC in regulating asymmetric division and the specification of divergent CD8+ T lymphocyte fates early during an immune response.

The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation

“…Here we show that naïve Lis1-deficient CD8 + T cells can undergo division in response to microbial infection in vivo , giving rise to daughter cells with a ‘pre-memory’ phenotype (CD8 lo IL-2Rα lo CD62L hi ); however, these 1 st division pre-memory cells appear to fail to continue differentiating into mature memory cells. These findings are consistent with the idea that acquisition of a pre-memory phenotype and the corresponding transcriptional program (4) may not be sufficient for a cell to become a memory lymphocyte (35) and underscore the plasticity of these cells early during their differentiation. However, the mechanisms that preclude Lis1-deficient CD8 + T cells that exhibit a pre-memory phenotype from acquiring the mature memory fate remain unclear.…”

Asymmetric Cell Division in T Lymphocyte Fate Diversification

“…Our recent work characterizing CD8 + T lymphocytes deficient in either isoform of the evolutionary conserved polarity protein, atypical protein kinase C (aPKC), has provided some of the first evidence suggesting that asymmetric division is an important first step in specifying T lymphocyte fates [29]. The aPKC isoforms - PKCζ and PKλ/ι - have been identified as important regulators of asymmetry in Drosophila and C. elegans (Box 1) and function during the first division of activated naïve CD8 + T lymphocytes to mediate asymmetric segregation of effector fate-associated factors, including IL-2Rα, IFNγR, and T-bet.…”

“…Loss of either aPKC isoform increased the symmetric distribution of these effector fate-associated molecules, resulting in a striking reduction in the molecular heterogeneity exhibited by individual cells that had undergone their first division and increased the proportion of effector-fated precursor cells. Although asymmetric division was only partially reduced, the subsequent alterations to the initial balance of effector-versus memory-fated precursor cells increased differentiation towards the effector T lymphocyte fates at the expense of memory T cell formation [29]. While complete ablation of asymmetric division would be necessary to definitively test the full extent of its role in cell fate specification, the currently available data suggest that asymmetric division, by virtue of excluding important effector fate-associated factors from one of the two nascent daughter cells, enables the simultaneous generation of effector- and memory-fated precursor cells.…”

“…T-bet can be asymmetrically degraded during the first division by activated naïve CD4 + T cells as a result of unequal distribution of the proteasome degradation machinery [32]. Because pseudo-substrate inhibition of PKCζ has been shown to reduce asymmetric division in CD4 + T lymphocytes [32], it is intriguing to speculate that asymmetric division may play a functionally important role in CD4 + T cell fate specification, similar to that observed in CD8 + T cells [29]. In this way, asymmetric division might also specify heterogeneous CD4 + T cell fates at the first division and potentiate divergent pathways of differentiation into T H 1/T EM or T FH /T CM cell fates; this hypothesis, however, remains to be addressed experimentally.…”

“…Additional lymphocyte subsets, including non-circulating tissue resident memory T cells [38, 39] and long-lived effector CD8 + T lymphocytes [29, 40, 41], have also been identified after acute infection; however, the ontogeny of these subsets remains less defined (Figure 1A). The observation that memory CD8 + T lymphocytes can undergo asymmetric division upon rechallenge [42] raises the possibility that additional asymmetric divisions during the primary immune response may mediate further divergence of early responding T cells into these additional effector and memory lineages.…”