NKG2D-mediated cytotoxicity toward oligodendrocytes suggests a mechanism for tissue injury in multiple sclerosis.
NKG2D is an activating or coactivating receptor expressed on human natural killer (NK) cells, CD8+ T cells, and gamma/delta 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, gamma/delta 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.
Saikali
Philippe
P
Neuroimmunology Unit, Montreal Neurological Institute, Montreal, Quebec, Canada H3A 2B4.
Antel
Jack P
JP
Newcombe
Jia
J
Chen
Zhihong
Z
Freedman
Mark
M
Blain
Manon
M
Cayrol
Romain
R
Prat
Alexandre
A
Hall
Jeffery A
JA
Arbour
Nathalie
N
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009836:Oligodendroglia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D055607:Receptors, Natural Killer Cell
D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell