Abstract
Migration of encephalitogenic CD4+ T lymphocytes across the blood-brain barrier is an essential step in the pathogenesis of multiple sclerosis (MS). We here demonstrate that expression of the co-stimulatory receptor NKG2D defines a subpopulation of CD4+ T cells with elevated levels of markers for migration, activation, and cytolytic capacity especially when derived from MS patients. Furthermore, CD4+NKG2D+ cells produce high levels of proinflammatory IFN-γ and IL-17 upon stimulation. NKG2D promotes the capacity of CD4+NKG2D+ cells to migrate across endothelial cells in an in vitro model of the blood-brain barrier. CD4+NKG2D+ T cells are enriched in the cerebrospinal fluid of MS patients, and a significant number of CD4+ T cells in MS lesions coexpress NKG2D. We further elucidated the role of CD4+NKG2D+ T cells in the mouse system. NKG2D blockade restricted central nervous system migration of T lymphocytes in vivo, leading to a significant decrease in the clinical and pathologic severity of experimental autoimmune encephalomyelitis, an animal model of MS. Blockade of NKG2D reduced killing of cultivated mouse oligodendrocytes by activated CD4+ T cells. Taken together, we identify CD4+NKG2D+ cells as a subpopulation of T helper cells with enhanced migratory, encephalitogenic and cytotoxic properties involved in inflammatory CNS lesion development.
Highlights
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic inflammatory disorders of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal degeneration
A pathogenic role has been postulated for CD4+NKG2D+ T cells under autoinflammatory conditions, raising the question of whether this distinct immune cell subset might be involved in the pathophysiology of multiple sclerosis (MS)
CD4+NKG2D+ T cells derived from the peripheral blood of treatment-naïve, RRMS patients with high disease activity expressed even higher levels of these markers
Summary
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic inflammatory disorders of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal degeneration. CD4+NKG2D+ T cells have been reported to play a pathogenic role in autoimmune disorders such as Crohn’s disease [6] or rheumatoid arthritis (RA) [10] and their respective animal models [11,12]. These CD4+NKG2D+ cells are expanded in the peripheral blood and especially in the respective target organs. They exert TCRindependent cytotoxic activity against NKG2D ligandexpressing target cells and have been shown to produce Th1 and Th17 cytokines both in RA and in Crohn’s disease [6,10,12,13]. A previous study [14] suggested an immunoregulatory role of CD4+NKG2D+ T cells with predominant production of IL-10 under polyclonal stimulation
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