德国大学医院临床神经免疫学研究所Naoto Kawakami和Martin Kerschensteiner研究团队合作利用一项全基因组体内CRISPR筛选，确定了多发性硬化症(MS)模型中T细胞向中枢神经系统迁移的基本调节因子。该项研究成果发表在2023年9月14日出版的《自然—神经科学》上。

他们在大鼠MS模型中进行了全基因组的体内CRISPR筛选，发现了T细胞向中枢神经系统迁移的5个基本刹车因子和18个基本促进因子。虽然转录因子ETS1通过控制T细胞的反应性来限制进入中枢神经系统，但以粘附分子α4-整合素、趋化因子受体CXCR3和GRK2激酶为中心的三个功能模块是自身反应性CD4+ T细胞迁移中枢神经系统所必需的。

MS患者的T细胞单细胞分析证实，这些基本调节因子的表达与CD4+ T细胞到达中枢神经系统的倾向相关。因此，我们的数据揭示了诱导MS病变的基本步骤的关键调节因子。

据悉，MS涉及自身反应性T细胞向中枢神经系统的浸润，但我们对调节这一过程的信号通路缺乏全面的了解。

附：英文原文

Title: A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model

Author: Kendirli, Arek, de la Rosa, Clara, Lmmle, Katrin F., Eglseer, Klara, Bauer, Isabel J., Kavaka, Vladyslav, Winklmeier, Stephan, Zhuo, La, Wichmann, Christian, Gerdes, Lisa Ann, Kmpfel, Tania, Dornmair, Klaus, Beltrn, Eduardo, Kerschensteiner, Martin, Kawakami, Naoto

Issue&Volume: 2023-09-14

Abstract: Multiple sclerosis (MS) involves the infiltration of autoreactive T cells into the CNS, yet we lack a comprehensive understanding of the signaling pathways that regulate this process. Here, we conducted a genome-wide in vivo CRISPR screen in a rat MS model and identified 5 essential brakes and 18 essential facilitators of T cell migration to the CNS. While the transcription factor ETS1 limits entry to the CNS by controlling T cell responsiveness, three functional modules, centered around the adhesion molecule α4-integrin, the chemokine receptor CXCR3 and the GRK2 kinase, are required for CNS migration of autoreactive CD4+ T cells. Single-cell analysis of T cells from individuals with MS confirmed that the expression of these essential regulators correlates with the propensity of CD4+ T cells to reach the CNS. Our data thus reveal key regulators of the fundamental step in the induction of MS lesions. Multiple sclerosis (MS) lesions are initiated by the infiltration of T cells to the CNS. Here, Kendirli et al. use a genome-wide CRISPR screen in an MS model to define the molecules that regulate T cell entry to the CNS.

DOI: 10.1038/s41593-023-01432-2

Source: https://www.nature.com/articles/s41593-023-01432-2