Activation of human NK cells by the bacterial pathogen-associated molecular pattern muramyl dipeptide.
Muramyl dipeptide (MDP) is a bacterial pathogen associated molecular pattern derived from both Gram-positive and -negative bacteria. It is a specific ligand for nuclear oligomerization domain 2, a pattern recognition receptor best characterized for its role in immunosurveillance in the gut. In this study, we demonstrate that human peripheral blood NK cells express nuclear oligomerization domain 2 and respond to MDP. NK cells naturally internalize MDP leading to direct cell activation, including signaling through NFkappaB: characterized by p50/p65 heterodimers at early stimulations times and sustained activation of p50 homodimers. Moreover, MDP synergizes with IFN-alpha and IL-12 to activate NK cells and stimulate IFN-gamma secretion, suggesting a role for accessory cells in induction of an optimal NK cell response. Although IL-12 costimulation leads to a greater IFN-gamma response by NK cells, higher levels of CD69 in response to MDP are induced in the presence of IFN-alpha, suggesting that different pathogen-induced cytokine profiles will affect downstream NK cell responses. In contrast, MDP alone or in combination with either IFN-alpha or IL-12 only poorly increases NK cell cytotoxicity. In summary, this report identifies MDP as a bacterial pathogen associated molecular pattern that activates human NK cells.
Athié-Morales
Verónica
V
Xoma Ireland Limited, Dublin, Ireland.
O'Connor
Geraldine M
GM
Gardiner
Clair M
CM
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D004705:Endocytosis / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000096:biosynthesis / Q000502:physiology; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000378:metabolism / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism
D016898:Interferon-alpha; D052002:NF-kappa B p50 Subunit; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D020569:Proto-Oncogene Proteins c-rel; D051192:Receptors, Pattern Recognition; D051996:Transcription Factor RelA; D000119:Acetylmuramyl-Alanyl-Isoglutamine