自分泌促炎IL-10启动肺特异性Th2反应吸入过敏原诱导过敏性哮喘

Kun He, Zhongli Xu, W. MacDonald, A. Ray, Wei Chen, B. Lambrecht, Amanda C. Poholek
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引用次数: 0

摘要

过敏性哮喘仍然是儿童和成人的重大健康负担。CD4 +Th2细胞是疾病的关键驱动因素,但支持启动Th2细胞对环境过敏原反应的机制尚不清楚。我们证明了转录抑制因子Blimp-1对促进肺中Th2细胞吸入而不是全身或皮下递送过敏原有明显的要求。通过对屋尘螨(HDM)特异性T细胞反应的时间、空间和单细胞转录组学追踪,研究人员发现,吸入HDM可驱动肺中GATA3上调和随后Th2分化所需的早期Blimp-1表达,这与IL2Rα表达一致。Blimp-1的表达仍然局限于hdm特异性Treg和Th2细胞,但重要的是Th2细胞的维持是必不可少的。我们发现,吸入过敏原诱导STAT激活模式,在GATA3 +过敏原特异性T细胞中,短暂的pSTAT5伴随持续的pSTAT3,这对于在淋巴结T细胞启动的早期阶段诱导Blimp-1至关重要。IL2Rα与IL10Rα信号直接作用于过敏原特异性T细胞,驱动Th2细胞分化。此外,来自过敏原特异性T细胞的IL-10足以诱导Th2细胞,这表明IL-10的自分泌或旁分泌环支持Blimp-1调节T- b边界的GATA3上调和随后的Th2分化。这些数据阐明了启动Th2对吸入过敏原反应的步骤,并确定了IL-10和Blimp-1驱动炎症T细胞对环境抗原反应的意外促炎需求。
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Autocrine pro-inflammatory IL-10 initiates lung-specific Th2 responses to inhaled allergen to induce allergic asthma
Allergic asthma remains a significant health burden for both children and adults. CD4 +Th2 cells are critical drivers of disease, yet the mechanisms that support initiation of the Th2 cell response to environmental allergens are not well understood. We demonstrated a distinct requirement for the transcriptional repressor Blimp-1 to promote Th2 cells in the lung to inhaled but not systemically or subcutaneously delivered allergens. Using temporal, spatial and single cell transcriptomic tracking of house dust mite (HDM) specific T cell responses, we demonstrate that inhalation of HDM drove early Blimp-1 expression necessary for GATA3 upregulation and subsequent Th2 differentiation in the lung that coincides with IL2Rα expression. Blimp-1 expression remains confined to HDM-specific Treg and Th2 cells that traffic to the lung but importantly is dispensable for Th2 cell maintenance. We found that inhaled allergens induce a pattern of STAT activation with transient pSTAT5 concomitant with sustained pSTAT3 within GATA3 +allergen-specific T cells, which is critical for the induction of Blimp-1 during the earliest phase of T cell priming in the lymph node. IL2Rα cooperates with IL10Rα signaling acting directly on allergen specific T cells to drive Th2 cell differentiation. Furthermore, IL-10 derived from allergen specific T cells was sufficient to induce Th2 cells suggesting an autocrine or paracrine loop of IL-10 supports Blimp-1 to regulate GATA3 upregulation at the T-B border and subsequent Th2 differentiation. These data shed light on the steps initiating Th2 responses to inhaled allergens and identify an unexpected pro-inflammatory requirement for IL-10 and Blimp-1 driving inflammatory T cell responses to environmental antigens.
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