Neuropeptide CGRP limits ILC2 responses and constrains type 2 inflammation

Innate and adaptive lymphocytes work in concert to maintain tissue homeostasis and to mediate host defense at mucosal barriers. Herein, we used single cell analysis to show substantial diversity of gene expression in ILCs and T helper cells during a helminth infection in the lung. Notably, we found that the Calca gene, which is spliced to generate the neuropeptide CGRP, was selectively transcribed in ILC2s and Th2 cells in an activation dependent manner. The Calca locus acquired chromatin accessibility at the ILC2 precursor stage and is pre-programmed for rapid production of CGRP upon ILC2 activation. CGRP globally antagonized actions of neuromedin U (NMU) and the alarmin IL-33. However, CGRP selectively acted in concert with NMU and IL-33 to promote IL-5 expression, but not IL-13. The complex interplay among neuropeptides and alarmin fine-tunes type 2 immune responses and will undoubtedly become more relevant as therapeutic neuropeptide blockade advances in the clinic. Overall design: Integrated analysis of transcriptome and epigenome data from ILCs and Th cells in steady or activated conditions

固有淋巴细胞（Innate Lymphoid Cells, ILCs）与适应性淋巴细胞协同作用，以维持组织稳态并在黏膜屏障处介导宿主防御反应。本研究借助单细胞分析技术，揭示了肺脏蠕虫感染过程中，ILCs与辅助T细胞（T helper cells）的基因表达存在显著异质性。值得注意的是，本研究发现经剪接可产生神经肽降钙素基因相关肽（Calcitonin Gene-Related Peptide, CGRP）的Calca基因，在ILC2s与Th2细胞中以激活依赖的方式被选择性转录。Calca基因座在ILC2前体细胞阶段即获得染色质可及性，预先编程使得ILC2在激活后可快速合成CGRP。CGRP可全局拮抗神经介素U（Neuromedin U, NMU）与警报素IL-33的生物学活性；然而，CGRP却可选择性地与NMU及IL-33协同作用，促进IL-5的表达，而非IL-13。神经肽与警报素之间的复杂相互作用可精细调控2型免疫应答，且随着临床治疗性神经肽阻断疗法的发展，其研究价值无疑将进一步凸显。整体实验设计：对稳态或激活状态下的ILCs与辅助T细胞的转录组及表观基因组数据进行整合分析。