UC San Diego
Regulation of Asymmetric Division and CD8-positive T Lymphocyte Fate Specification by Atypical Protein Kinase C
- Author(s): Metz, Patrick John
- et al.
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 nascent daughter cells to inherit unequal amounts of fate- determining proteins and thereby acquire distinct fates from their inception. Here, we show that the atypical protein kinase C (aPKC) isoforms, PKC[zeta] and PKC[lambda]/l, have compensatory roles in regulating asymmetric CD8⁺ T lymphocyte division. Individual or complete loss of aPKC disrupts asymmetric division by activated CD8⁺ T lymphocytes and results in aberrant acquisition of a 'pre-effector' transcriptional program in lymphocytes that have undergone their first division in vivo. These alterations were associated with reduced molecular heterogeneity, detected by single-cell gene expression analyses, and increased proportions of daughter cells that inherited high amounts of effector fate- associated factors including interleukin-2 receptor [alpha], T-bet, interferon-[gamma] receptor, and interferon regulatory factor 4. The increased presence of pre-effector daughter cells at the first division enhances differentiation toward the effector fates, and the corresponding loss of 'pre-memory' daughter cells that exclude these important effector fate-associated factors subsequently decreases acquisition of the memory fates. Together, these results demonstrate an important role for aPKC in regulating asymmetric division and the specification of divergent CD8⁺ T lymphocyte fates at the initiation of the adaptive immune response