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

Abstract (Expand)

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 alpha4-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.

Authors: A. Kendirli, C. de la Rosa, K. F. Lammle, K. Eglseer, I. J. Bauer, V. Kavaka, S. Winklmeier, L. Zhuo, C. Wichmann, L. A. Gerdes, T. Kumpfel, K. Dornmair, E. Beltran, M. Kerschensteiner, N. Kawakami

Date Published: 4th Oct 2023

Publication Type: Journal

Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity.

Abstract (Expand)

Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an … experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6(+), and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.

Authors: M. Hiltensperger, E. Beltran, R. Kant, S. Tyystjarvi, G. Lepennetier, H. Dominguez Moreno, I. J. Bauer, S. Grassmann, S. Jarosch, K. Schober, V. R. Buchholz, S. Kenet, C. Gasperi, R. Ollinger, R. Rad, A. Muschaweckh, C. Sie, L. Aly, B. Knier, G. Garg, A. M. Afzali, L. A. Gerdes, T. Kumpfel, S. Franzenburg, N. Kawakami, B. Hemmer, D. H. Busch, T. Misgeld, K. Dornmair, T. Korn

Date Published: 9th Jun 2021

Publication Type: Journal

Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis.

Abstract (Expand)

Multiple sclerosis (MS) is a disabling disease of the CNS. Inflammatory features of MS include lymphocyte accumulations in the CNS and cerebrospinal fluid (CSF). The preclinical events leading to … established MS are still enigmatic. Here we compared gene expression patterns of CSF cells from MS-discordant monozygotic twin pairs. Six "healthy" co-twins, who carry a maximal familial risk for developing MS, showed subclinical neuroinflammation (SCNI) with small MRI lesions. Four of these subjects had oligoclonal bands (OCBs). By single-cell RNA sequencing of 2752 CSF cells, we identified clonally expanded CD8+ T cells, plasmablasts, and, to a lesser extent, CD4+ T cells not only from MS patients but also from subjects with SCNI. In contrast to nonexpanded T cells, clonally expanded T cells showed characteristics of activated tissue-resident memory T (TRM) cells. The TRM-like phenotype was detectable already in cells from SCNI subjects but more pronounced in cells from patients with definite MS. Expanded plasmablast clones were detected only in MS and SCNI subjects with OCBs. Our data provide evidence for very early concomitant activation of 3 components of the adaptive immune system in MS, with a notable contribution of clonally expanded TRM-like CD8+ cells.

Authors: E. Beltran, L. A. Gerdes, J. Hansen, A. Flierl-Hecht, S. Krebs, H. Blum, B. Ertl-Wagner, F. Barkhof, T. Kumpfel, R. Hohlfeld, K. Dornmair

Date Published: 1st Nov 2019

Publication Type: Journal

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