Metz Patrick J, Lopez Justine, Kim Stephanie H, Akimoto Kazunori, Ohno Shigeo, Chang John T
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Department of Molecular Biology, Yokohama City University School of Medicine, Kanazawa, Yokohama, Kanagawa Prefecture 236-0027, Japan.
Sci Rep. 2016 Jan 14;6:19182. doi: 10.1038/srep19182.
Naïve CD8(+) T lymphocytes responding to microbial pathogens give rise to effector T cells that provide acute defense and memory T cells that provide long-lived immunity. Upon activation, CD8(+) T lymphocytes can undergo asymmetric division, unequally distributing factors to the nascent daughter cells that influence their eventual fate towards the effector or memory lineages. Individual loss of either atypical protein kinase C (aPKC) isoform, PKCζ or PKCλ/ι, partially impairs asymmetric divisions and increases CD8(+) T lymphocyte differentiation toward a long-lived effector fate at the expense of memory T cell formation. Here, we show that deletion of both aPKC isoforms resulted in a deficit in asymmetric divisions, increasing the proportion of daughter cells that inherit high amounts of effector fate-associated molecules, IL-2Rα, T-bet, IFNγR, and interferon regulatory factor 4 (IRF4). However, unlike CD8(+) T cells deficient in only one aPKC isoform, complete loss of aPKC unexpectedly increased CD8(+) T cell differentiation toward a short-lived, terminal effector fate, as evidenced by increased rates of apoptosis and decreased expression of Eomes and Bcl2 early during the immune response. Together, these results provide evidence for an important role for asymmetric division in CD8(+) T lymphocyte fate specification by regulating the balance between effector and memory precursors at the initiation of the adaptive immune response.
对微生物病原体产生应答的初始CD8(+) T淋巴细胞会分化为提供急性防御的效应T细胞和提供长期免疫的记忆T细胞。激活后，CD8(+) T淋巴细胞可进行不对称分裂，将各种因子不均等地分配给新生子细胞，从而影响它们最终向效应细胞或记忆细胞谱系的分化命运。单独缺失任一非典型蛋白激酶C（aPKC）亚型，即PKCζ或PKCλ/ι，都会部分损害不对称分裂，并增加CD8(+) T淋巴细胞向长寿效应细胞命运的分化，同时以牺牲记忆T细胞形成为代价。在此，我们表明，同时缺失两种aPKC亚型会导致不对称分裂功能缺陷，增加继承大量与效应细胞命运相关分子（白细胞介素-2受体α、T-bet、干扰素γ受体和干扰素调节因子4（IRF4））的子细胞比例。然而，与仅缺失一种aPKC亚型的CD8(+) T细胞不同，aPKC的完全缺失意外地增加了CD8(+) T细胞向短命的终末效应细胞命运的分化，这在免疫应答早期表现为凋亡率增加以及Eomes和Bcl2表达降低。总之，这些结果证明了不对称分裂在CD8(+) T淋巴细胞命运决定中发挥重要作用，即在适应性免疫应答启动时调节效应细胞和记忆细胞前体之间的平衡。
