THE BROAD INSTITUTE, INC.;XAVIER, Ramnik;DING, Jiarui;THE GENERAL HOSPITAL CORPORATION;MASSACHUSETTS INSTITUTE OF TECHNOLOGY
发明人:
XU, Heping,REGEV, Aviv
申请号：
USUS2020/022803
公开号：
WO2020/186235A1
申请日:
2020.03.13
申请国别(地区):
US
年份:
2020
代理人:
摘要：
The present invention provides novel compositions and methods based on the discovery of the mechanisms and gene expression programs associated with homeostatic ILC2s and proinflammatory ILC2s that drive tissue inflammation. Immune signaling abnormalities in the small intestine can trigger chronic type 2 inflammation. Applicants analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA-seq at steady state and after induction of a type 2 inflammatory reaction to ovalbumin. Cell type composition and cell programs shifted in response to inflammation, especially in ILC2s. A key transcript in the inflammation-induced program in intestinal KLRG1+ ILC2s was exon 5 of Calca, encoding the alpha-calcitonin gene-related peptide (a-CGRP). a-CGRP antagonized IL-25 -induced activation of intestinal ILC2s and reduced their frequency in an ovalbumin reaction model. α-CGRP activated a cAMP response, which suppressed ILC2 proliferation. In homeostasis, α-CGRP was expressed by two subsets of ChAT+ enteric neurons, and genetic perturbation of α-CGRP increased the proportion of intestinal ILC2s and of Tuft cells. The results demonstrate that a-CGRP-mediated neuronal signaling suppresses ILC2 expansion and maintains type 2 immunity homeostasis.La présente invention concerne de nouvelles compositions et de nouveaux procédés basés sur la découverte des mécanismes et des programmes d'expression génique associés aux ILC2 homéostatiques et aux ILC2 pro-inflammatoires qui provoquent une inflammation tissulaire. Des anomalies de signalisation immunitaire dans l'intestin grêle peuvent déclencher une inflammation de type 2 chronique. Les demandeurs ont analysé 58 067 cellules immunitaires d'intestin grêle de souris par séquençage d'ARN de cellule individuelle à l'état stable et après l'induction d'une réaction inflammatoire de type 2 à l'ovalbumine. La composition de type cellulaire et les programmes cellulaires ont changé en réponse à une inflammation, en particulier dans les
