Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK.
IONTAS, The Works, Unity Campus, Cambridge, CB22 3EF, UK.
Eur J Immunol. 2022 Jul;52(7):1058-1068. doi: 10.1002/eji.202149781. Epub 2022 Apr 29.
The RNA-binding protein polypyrimidine tract binding protein 1 (PTBP1) has been found to have roles in CD4 T-cell activation, but its function in CD8 T cells remains untested. We show it is dispensable for the development of naïve mouse CD8 T cells, but is necessary for the optimal expansion and production of effector molecules by antigen-specific CD8 T cells in vivo. PTBP1 has an essential role in regulating the early events following activation of the naïve CD8 T cell leading to IL-2 and TNF production. It is also required to protect activated CD8 T cells from apoptosis. PTBP1 controls alternative splicing of over 400 genes in naïve CD8 T cells in addition to regulating the abundance of ∼200 mRNAs. PTBP1 is required for the nuclear accumulation of c-Fos, NFATc2, and NFATc3, but not NFATc1. This selective effect on NFAT proteins correlates with PTBP1-promoted expression of the shorter Aβ1 isoform and exon 13 skipped Aβ2 isoform of the catalytic A-subunit of calcineurin phosphatase. These findings reveal a crucial role for PTBP1 in regulating CD8 T-cell activation.
RNA 结合蛋白多嘧啶 tract 结合蛋白 1（PTBP1）已被发现在 CD4 T 细胞活化中具有作用，但它在 CD8 T 细胞中的功能尚未得到测试。我们发现它对于幼稚的小鼠 CD8 T 细胞的发育不是必需的，但对于体内抗原特异性 CD8 T 细胞的最佳扩增和效应分子的产生是必需的。PTBP1 在调节幼稚 CD8 T 细胞活化后的早期事件中具有重要作用，导致 IL-2 和 TNF 的产生。它还需要保护活化的 CD8 T 细胞免于凋亡。PTBP1 控制着幼稚 CD8 T 细胞中超过 400 个基因的可变剪接，除了调节大约 200 个 mRNA 的丰度。PTBP1 对于 c-Fos、NFATc2 和 NFATc3 的核积累是必需的，但对于 NFATc1 不是必需的。这种对 NFAT 蛋白的选择性影响与 PTBP1 促进 calcineurin 磷酸酶的催化 A 亚基的较短 Aβ1 同工型和跳过外显子 13 的 Aβ2 同工型的表达相关。这些发现揭示了 PTBP1 在调节 CD8 T 细胞活化中的关键作用。
