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The Journal of Neuroscience, January 31, 2007, 27(5):1220-1228; doi:10.1523/JNEUROSCI.4402-06.2007

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Neurobiology of Disease
NKG2D-Mediated Cytotoxicity toward Oligodendrocytes Suggests a Mechanism for Tissue Injury in Multiple Sclerosis

Philippe Saikali,¹ Jack P. Antel,¹ Jia Newcombe,³ Zhihong Chen,⁴ Mark Freedman,⁴ Manon Blain,¹ Romain Cayrol,⁵ Alexandre Prat,⁵ Jeffery A. Hall,² and Nathalie Arbour^1,5

¹Neuroimmunology Unit, Montreal Neurological Institute, and ²Division of Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2B4, ³NeuroResource, University College London, Institute of Neurology, London WC1N 1PJ, United Kingdom, ⁴Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada K1H 8L6, and ⁵Research Center-Centre Hospitalier de l'Université de Montréal, University of Montreal, Montreal, Quebec, Canada H2L 4M1

Correspondence should be addressed to Nathalie Arbour, Research Center-Centre Hospitalier de l'Université de Montréal, University of Montreal, Pavilion JA DeSeve (Y-3609), 1560 Sherbrooke East, Montreal, Quebec, Canada H2L 4M1. Email: nathalie.arbour{at}umontreal.ca

NKG2D is an activating or coactivating receptor expressed on human natural killer (NK) cells, CD8⁺ T cells, and / T cells. NKG2D ligands have been detected on many tumor cell types and can be induced on nontransformed cells by environmental signals including DNA damage and inflammation. We investigated the contribution of NKG2D–NKG2D ligand interaction on CNS-directed immune responses. We observed that primary cultures of human adult oligodendrocytes and fetal astrocytes expressed ligands for NKG2D in vitro whereas neurons, microglia, and adult astrocytes did not. Disruption of the NKG2D–NKG2D ligand interaction using blocking antibodies significantly inhibited killing of primary human oligodendrocytes mediated by activated human NK cells, / T cells, and allo-reactive CD8⁺ T cells. NKG2D ligands [major histocompatibility complex class I chain-related molecules A and B (MICA/B)] were detected in groups of cells and colocalized with an oligodendrocyte marker (adenomatous polyposis coli) in white matter sections obtained from multiple sclerosis lesions but not in normal control samples. CD8⁺ T cells could be detected in close proximity to MICA/B+ cells within multiple sclerosis lesions, supporting an in vivo interaction between these immune effectors and stressed MICA/B-expressing oligodendrocytes. These results imply that NKG2D–NKG2D ligand interaction can potentially contribute to cytotoxic responses mediated by activated immune effector cells in the inflamed CNS, as observed in multiple sclerosis.

Key words: oligodendrocytes; multiple sclerosis; human; astrocytes; autoimmunity; lymphocytes

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Received Aug. 16, 2006; revised Dec. 15, 2006; accepted Dec. 24, 2006.

Correspondence should be addressed to Nathalie Arbour, Research Center-Centre Hospitalier de l'Université de Montréal, University of Montreal, Pavilion JA DeSeve (Y-3609), 1560 Sherbrooke East, Montreal, Quebec, Canada H2L 4M1. Email: nathalie.arbour{at}umontreal.ca

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