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Neuroimmunology

Navigating T cell brain entry in MS

Nature Neuroscience volume 26, pages 1661–1662 (2023)Cite this article

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that is driven by autoreactive lymphocytes. An in vivo CRISPR screen of T cell infiltration in a rat model of MS now identifies the genetic modules that control this key step in the immunopathology of MS.

Multiple sclerosis is a chronic neurological condition characterized by autoimmune degradation of myelin sheaths and killing of oligodendrocytes. While aspects of its etiology remain unclear, a consensus has emerged that the infiltration of autoreactive T cells into the CNS has an important role in the initiation and progression of the disease1. This consensus derives from studies of experimental autoimmune encephalomyelitis (EAE) — a rodent model of MS — and genome-wide association studies in patients with MS, which have shown that genetic modifiers of T cell function increase disease susceptibility2. Definitive clinical evidence for the autoimmune hypothesis came from the development of immunotherapeutics such as anti-α4 integrin antibody treatment. In preclinical studies with the EAE model, blockade of α4β1 integrin prevented T cell migration to the CNS and reduced pathology3, with the clinical counterpart, natalizumab, proving effective in the treatment of relapsing-remitting MS4. These advances not only confirmed the autoimmune hypothesis of MS and provided an effective treatment, but also validated T cell migration molecules as drug targets. Until now, such targets have been identified only using candidate-based approaches, but in this issue of Nature Neuroscience, Kawakami et al.5 describe, to our knowledge, the first genome-wide in vivo CRISPR screen of T cell infiltration into the brain. This work identifies previously unknown gene modules that govern the entry of encephalitogenic autoreactive CD4 T cells into the rat CNS. Furthermore, by using overlapping T cell receptor (TCR) sequences as barcodes to identify CNS-capable T cell clones, the authors show that the CNS entry modules found in the rat screen correlate with expression in patients with MS, providing exciting clinical validation of the new targets.

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Fig. 1: Identifying the molecular mechanisms that regulate CD4 T cell migration to the CNS during MS.

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  1. Department of Pathology, University of Cambridge, Cambridge, UK

    Magda Ali & Adrian Liston

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  1. Magda Ali
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  2. Adrian Liston
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Correspondence to Adrian Liston.

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The authors declare no competing interests.

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Ali, M., Liston, A. Navigating T cell brain entry in MS. Nat Neurosci 26, 1661–1662 (2023). https://doi.org/10.1038/s41593-023-01433-1

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