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Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-TFH cells.
Science Immunology ( IF 17.6 ) Pub Date : 2019-09-13 , DOI: 10.1126/sciimmunol.aaw7636
Amber Papillion 1 , Michael D Powell 2, 3 , Danielle A Chisolm 4 , Holly Bachus 1 , Michael J Fuller 1 , Amy S Weinmann 4 , Alejandro Villarino 5 , John J O'Shea 5 , Beatriz León 4 , Kenneth J Oestreich 2, 6, 7 , André Ballesteros-Tato 1
Affiliation  

Sustained T cell receptor (TCR) stimulation is required for maintaining germinal center T follicular helper (GC-TFH) cells. Paradoxically, TCR activation induces interleukin-2 receptor (IL-2R) expression and IL-2 production, thereby initiating a feedback loop of IL-2 signaling that normally inhibits TFH cells. It is unclear how GC-TFH cells can receive prolonged TCR signaling without succumbing to the detrimental effects of IL-2. Using an influenza infection model, we show here that GC-TFH cells secreted large amounts of IL-2 but responded poorly to it. To maintain their IL-2 hyporesponsiveness, GC-TFH cells required intrinsic IL-6 signaling. Mechanistically, we found that IL-6 inhibited up-regulation of IL-2Rβ (CD122) by preventing association of STAT5 with the Il2rb locus, thus allowing GC-TFH cells to receive sustained TCR signaling and produce IL-2 without initiating a TCR/IL-2 inhibitory feedback loop. Collectively, our results identify a regulatory mechanism that controls the generation of GC-TFH cells.

中文翻译:

IL-6 抑制 IL-2 反应是 GC-TFH 细胞生成所必需的。

维持生发中心滤泡辅助 T (GC-TFH) 细胞需要持续的 T 细胞受体 (TCR) 刺激。矛盾的是,TCR 激活会诱导白细胞介素 2 受体 (IL-2R) 表达和 IL-2 产生,从而启动通常抑制 TFH 细胞的 IL-2 信号反馈回路。目前尚不清楚 GC-TFH 细胞如何能够接收延长的 TCR 信号而不屈服于 IL-2 的有害影响。使用流感感染模型,我们在此表明​​ GC-TFH 细胞分泌大量 IL-2,但对其反应不佳。为了维持 IL-2 低反应性,GC-TFH 细胞需要内在的 IL-6 信号传导。从机制上讲,我们发现 IL-6 通过阻止 STAT5 与 Il2rb 基因座的关联来抑制 IL-2Rβ (CD122) 的上调,从而允许 GC-TFH 细胞接收持续的 TCR 信号传导并产生 IL-2,而不启动 TCR/IL-2 抑制反馈循环。总的来说,我们的结果确定了控制 GC-TFH 细胞生成的调节机制。
更新日期:2019-09-14
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