Harvard Medical School, Boston, MA 02115, USA; Immune Disease Institute, Boston, MA 02115, USA.
Immunity. 2010 Jan 29;32(1):79-90. doi: 10.1016/j.immuni.2009.11.012. Epub 2010 Jan 21.
Interleukin(IL)-2 and inflammation regulate effector and memory cytolytic T-lymphocyte (CTL) generation during infection. We demonstrate a complex interplay between IL-2 and inflammatory signals during CTL differentiation. IL-2 stimulation induced the transcription factor eomesodermin (Eomes), upregulated perforin (Prf1) transcription, and repressed re-expression of memory CTL markers Bcl6 and IL-7Ralpha. Binding of Eomes and STAT5 to Prf1 cis-regulatory regions correlated with transcriptional initiation (increased recruitment of RNA polymerase II to the Prf1 promoter). Inflammation (CpG, IL-12) enhanced expression of IL-2Ralpha and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7Ralpha repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2Ralpha-deficient effector CD8(+) T cells expressed more Bcl6 but less perforin and granzyme B, formed fewer KLRG-1(+) and T-bet-expressing CTL, and killed poorly. Thus, inflammation influences both effector and memory CTL differentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTL development.
白细胞介素(IL)-2 和炎症调节感染期间效应器和记忆细胞毒性 T 淋巴细胞 (CTL) 的生成。我们在 CTL 分化过程中证明了 IL-2 和炎症信号之间的复杂相互作用。IL-2 刺激诱导转录因子 eomesodermin (Eomes)，上调穿孔素 (Prf1) 转录，并抑制记忆 CTL 标志物 Bcl6 和 IL-7Ralpha 的重新表达。Eomes 和 STAT5 与 Prf1 顺式调控区的结合与转录起始相关（增加 RNA 聚合酶 II 到 Prf1 启动子的募集）。炎症（CpG、IL-12）增强了 IL-2Ralpha 和转录因子 T-bet 的表达，但在 IL-2 诱导晚期 Eomes 和穿孔素的同时，抑制了 IL-7Ralpha 的表达。在用淋巴细胞性脉络丛脑膜炎病毒感染小鼠后，IL-2Ralpha 缺陷的效应 CD8(+) T 细胞表达更多的 Bcl6，但表达更少的穿孔素和颗粒酶 B，形成更少的 KLRG-1(+) 和 T-bet 表达的 CTL，杀伤能力较差。因此，炎症既影响效应器 CTL 又影响记忆 CTL 的分化，而持续的 IL-2 刺激则促进效应器 CTL 的发育而牺牲记忆 CTL 的发育。
