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Mechanism of Neuroinflammation: Enhanced Cytotoxicity and IL-17 Production via CD46 Binding

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Abstract

The membrane co-factor protein CD46 is the cellular receptor for a number of pathogens including the human herpesvirus 6 (HHV-6). In addition to its function as an inhibitory complement receptor, engagement of CD46 in the context of T-cell receptor (TCR) signaling influences T-cell activation. Simultaneous cross-linking of the CD3/CD46 molecules led to differentiation of a unique population of CD4+ T-cell subset characterized by enhanced expressions of IFN-γ, IL-10, granzyme B, adhesion molecule MAdCAM-1 (alpha-4-beta-7), surface-bound cytokine LIGHT, and chemokine receptor CCR9. Multiple sclerosis is a chronic inflammatory neurodegenerative disorder of the central nervous system (CNS) with unknown etiology. The HHV-6 is a candidate pathogen in MS and uses the CD46 molecule as its receptor. We hypothesize that binding of the HHV-6 glycoprotein to CD46 may trigger a pro-inflammatory response that could contribute to CNS tissue damage. To address this question, we examined immunological parameters such as proliferation, cytokine production and cytotoxic functions in CD4+ T cells of healthy individuals and MS patients following CD3/CD46 co-engagement by using anti-CD3 and anti-CD46 monoclonal antibodies as surrogates to mimic T-cell receptor and CD46 signaling. Our results demonstrated that CD3/CD46 cross-linking induced expression of IL-1β and IL-17A in multiple sclerosis patient T cells. Additionally, increase in transient surface expression of lysosomal associated protein CD107a suggested enhanced CD4+ T-cell cytotoxic functions following CD3/CD46 co-stimulation. Collectively, this study demonstrated evidence to suggest a potential mechanism of virus-induced neuroinflammation that may be involved in MS disease pathogenesis.

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Authors and Affiliations

  1. Viral Immunology Section, NINDS, NIH, Bethesda, MD, 20892, USA

    Karen Yao, Jhanelle Graham, Yoshimi Akahata, Unsong Oh & Steven Jacobson

  2. Department of Biology, Johns Hopkins University, Baltimore, MD, 21218, USA

    Karen Yao

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  1. Karen Yao
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  2. Jhanelle Graham
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  3. Yoshimi Akahata
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  4. Unsong Oh
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  5. Steven Jacobson
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Correspondence to Steven Jacobson.

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Yao, K., Graham, J., Akahata, Y. et al. Mechanism of Neuroinflammation: Enhanced Cytotoxicity and IL-17 Production via CD46 Binding. J Neuroimmune Pharmacol 5, 469–478 (2010). https://doi.org/10.1007/s11481-010-9232-9

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  • DOI: https://doi.org/10.1007/s11481-010-9232-9

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