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Tissue-resident memory T cells invade the brain parenchyma in multiple sclerosis white matter lesions.
Fransen, Nina L; Hsiao, Cheng-Chih; van der Poel, Marlijn; Engelenburg, Hendrik J; Verdaasdonk, Kim; Vincenten, Maria C J; Remmerswaal, Ester B M; Kuhlmann, Tanja; Mason, Matthew R J; Hamann, Jörg; Smolders, Joost; Huitinga, Inge.
Afiliação
  • Fransen NL; Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
  • Hsiao CC; Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  • van der Poel M; Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
  • Engelenburg HJ; Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
  • Verdaasdonk K; Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
  • Vincenten MCJ; Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
  • Remmerswaal EBM; Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  • Kuhlmann T; Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  • Mason MRJ; Institute for Neuropathology, University Hospital Münster, Münster, Germany.
  • Hamann J; Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
  • Smolders J; Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
  • Huitinga I; Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Brain ; 143(6): 1714-1730, 2020 06 01.
Article em En | MEDLINE | ID: mdl-32400866
ABSTRACT
Multiple sclerosis is a chronic inflammatory, demyelinating disease, although it has been suggested that in the progressive late phase, inflammatory lesion activity declines. We recently showed in the Netherlands Brain Bank multiple sclerosis-autopsy cohort considerable ongoing inflammatory lesion activity also at the end stage of the disease, based on microglia/macrophage activity. We have now studied the role of T cells in this ongoing inflammatory lesion activity in chronic multiple sclerosis autopsy cases. We quantified T cells and perivascular T-cell cuffing at a standardized location in the medulla oblongata in 146 multiple sclerosis, 20 neurodegenerative control and 20 non-neurological control brain donors. In addition, we quantified CD3+, CD4+, and CD8+ T cells in 140 subcortical white matter lesions. The location of CD8+ T cells in either the perivascular space or the brain parenchyma was determined using CD8/laminin staining and confocal imaging. Finally, we analysed CD8+ T cells, isolated from fresh autopsy tissues from subcortical multiple sclerosis white matter lesions (n = 8), multiple sclerosis normal-appearing white matter (n = 7), and control white matter (n = 10), by flow cytometry. In normal-appearing white matter, the number of T cells was increased compared to control white matter. In active and mixed active/inactive lesions, the number of T cells was further augmented compared to normal-appearing white matter. Active and mixed active/inactive lesions were enriched for both CD4+ and CD8+ T cells, the latter being more abundant in all lesion types. Perivascular clustering of T cells in the medulla oblongata was only found in cases with a progressive disease course and correlated with a higher percentage of mixed active/inactive lesions and a higher lesion load compared to cases without perivascular clusters in the medulla oblongata. In all white matter samples, CD8+ T cells were located mostly in the perivascular space, whereas in mixed active/inactive lesions, 16.3% of the CD8+ T cells were encountered in the brain parenchyma. CD8+ T cells from mixed active/inactive lesions showed a tissue-resident memory phenotype with expression of CD69, CD103, CD44, CD49a, and PD-1 and absence of S1P1. They upregulated markers for homing (CXCR6), reactivation (Ki-67), and cytotoxicity (GPR56), yet lacked the cytolytic enzyme granzyme B. These data show that in chronic progressive multiple sclerosis cases, inflammatory lesion activity and demyelinated lesion load is associated with an increased number of T cells clustering in the perivascular space. Inflammatory active multiple sclerosis lesions are populated by CD8+ tissue-resident memory T cells, which show signs of reactivation and infiltration of the brain parenchyma.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos T CD8-Positivos / Substância Branca / Tecido Parenquimatoso / Esclerose Múltipla Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Brain Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfócitos T CD8-Positivos / Substância Branca / Tecido Parenquimatoso / Esclerose Múltipla Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Brain Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Holanda