Osteopontin associates with brain TRM-cell transcriptome and compartmentalization in donors with and without multiple sclerosis

Cheng-Chih Hsiao; Hendrik J Engelenburg; Aldo Jongejan; Jing Zhu; Baohong Zhang; Michael Mingueneau; Perry D Moerland; Inge Huitinga; Joost Smolders; Jörg Hamann

doi:10.1016/j.isci.2022.105785

Osteopontin associates with brain T_RM-cell transcriptome and compartmentalization in donors with and without multiple sclerosis

iScience. 2022 Dec 9;26(1):105785. doi: 10.1016/j.isci.2022.105785. eCollection 2023 Jan 20.

Authors

Cheng-Chih Hsiao^{1

2}, Hendrik J Engelenburg¹, Aldo Jongejan³, Jing Zhu⁴, Baohong Zhang⁴, Michael Mingueneau⁵, Perry D Moerland³, Inge Huitinga^{1

6}, Joost Smolders^{1

7}, Jörg Hamann^{1

2}

Affiliations

¹ Neuroimmunology Research Group, Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands.
² Department of Experimental Immunology, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, 1105 AZ Amsterdam, the Netherlands.
³ Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam University Medical Centers, 1105 AZ Amsterdam, the Netherlands.
⁴ Translational Biology, Biogen, Cambridge, MA 02142, USA.
⁵ Multiple Sclerosis and Neurorepair Research Unit, Biogen, Cambridge, MA 02142, USA.
⁶ Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, 1098 XH Amsterdam, the Netherlands.
⁷ MS Center ErasMS, Departments of Neurology and Immunology, Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands.

Abstract

The human brain is populated by perivascular T cells with a tissue-resident memory T (T_RM)-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated T cells from white and gray matter. RNA sequencing of CD8⁺ and CD4⁺ CD69⁺ T cells revealed T_RM-cell signatures. Notably, gene expression hardly differed between lesional and normal-appearing white matter T cells in MS brains. Genes up-regulated in brain T_RM cells were MS4A1 (CD20) and SPP1 (osteopontin, OPN). OPN is also abundantly expressed by microglia and has been shown to inhibit T cell activity. In line with their parenchymal localization and the increased presence of OPN in active MS lesions, we noticed a reduced production of inflammatory cytokines IL-2, TNF, and IFNγ by lesion-derived CD8⁺ and CD4⁺ T cells ex vivo. Our study reports traits of brain T_RM cells and reveals their tight control in MS lesions.

Keywords: Molecular neuroscience; Neuroscience; Omics; Transcriptomics.