A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model
Arek Kendirli, Clara de la Rosa, Katrin F. Lämmle, Klara Eglseer, Isabel Bauer, Vladyslav Kavaka, Stephan Winklmeier, La Zhuo, Christian Wichmann, Lisa Ann Gerdes, Tania Kümpfel, Klaus Dornmair, Eduardo Beltrán, Martin Kerschensteiner, Naoto Kawakami
Abstract
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.