美国国立卫生研究院Daniella M. Schwartz研究组取得一项新突破。他们的研究发现在辅助性T9（T_H9）细胞中，染色质动态可及性诱导STAT5和STAT6依赖性先天免疫功能以促进过敏性炎症。这一研究成果发表在2023年4月27日出版的国际学术期刊《自然—免疫学》上。

研究人员发现静息的T_H9细胞由STAT5和STAT6依赖的旁观者通路激活，而独立于T细胞受体（TCR）再刺激产生白细胞介素（IL）-9。这种机制在过敏患者的循环细胞中可见，并且仅限于最近激活的细胞。依赖于STAT5的Il9/IL9调节元件随着时间的推移发生重塑使位点失活。更广泛的“过敏T_H9”转录组学和表观基因组学基序也不稳定。在体内，T_H9细胞通过TCR非依赖性、STAT依赖性机制诱导气道炎症。在过敏患者中，T_H9细胞扩增与对JAK抑制剂的反应有关。

这些发现表明，T_H9细胞的不稳定性是旁观者激活的阴性检查点并在过敏发生时分解，对于TH9细胞扩增的过敏患者，应考虑使用JAK抑制剂治疗。

研究人员表示，过敏性疾病是威胁人类健康的常见问题之一。产生IL-9的TH9细胞促进过敏性炎症，但尚不完全清楚T_H9效应细胞的功能，其谱系不稳定性使其难以被研究。

附：英文原文

Title: Dynamic chromatin accessibility licenses STAT5- and STAT6-dependent innate-like function of TH9 cells to promote allergic inflammation

Author: Son, Aran, Meylan, Francoise, Gomez-Rodriguez, Julio, Kaul, Zenia, Sylvester, McKella, Falduto, Guido H., Vazquez, Estefania, Haque, Tamara, Kitakule, Moses M., Wang, Chujun, Manthiram, Kalpana, Qi, Chen-Feng, Cheng, Jun, Gurram, Rama K., Zhu, Jinfang, Schwartzberg, Pamela, Milner, Joshua D., Frischmeyer-Guerrerio, Pamela A., Schwartz, Daniella M.

Issue&Volume: 2023-04-27

Abstract: Allergic diseases are a major global health issue. Interleukin (IL)-9-producing helper T (TH9) cells promote allergic inflammation, yet TH9 cell effector functions are incompletely understood because their lineage instability makes them challenging to study. Here we found that resting TH9 cells produced IL-9 independently of T cell receptor (TCR) restimulation, due to STAT5- and STAT6-dependent bystander activation. This mechanism was seen in circulating cells from allergic patients and was restricted to recently activated cells. STAT5-dependent Il9/IL9 regulatory elements underwent remodeling over time, inactivating the locus. A broader ‘allergic TH9’ transcriptomic and epigenomic program was also unstable. In vivo, TH9 cells induced airway inflammation via TCR-independent, STAT-dependent mechanisms. In allergic patients, TH9 cell expansion was associated with responsiveness to JAK inhibitors. These findings suggest that TH9 cell instability is a negative checkpoint on bystander activation that breaks down in allergy and that JAK inhibitors should be considered for allergic patients with TH9 cell expansion.

DOI: 10.1038/s41590-023-01501-5

Source: https://www.nature.com/articles/s41590-023-01501-5