Mechanism of neuroinflammation: enhanced cytotoxicity and IL-17 production via CD46 binding.
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-gamma, 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-1beta 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.
Yao
Karen
K
Viral Immunology Section, NINDS, NIH, Bethesda, MD 20892, USA.
Graham
Jhanelle
J
Akahata
Yoshimi
Y
Oh
Unsong
U
Jacobson
Steven
S
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D015654:Herpesvirus 6, Human / Q000276:immunology / Q000502:physiology; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D051916:Membrane Cofactor Protein / Q000276:immunology / Q000502:physiology*; D009103:Multiple Sclerosis / Q000276:immunology / Q000503:physiopathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000503:physiopathology; D020078:Neurogenic Inflammation / Q000276:immunology* / Q000503:physiopathology; D019349:Roseolovirus Infections / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology
D020381:Interleukin-17; D051916:Membrane Cofactor Protein