Inhibitory receptor signals suppress ligation-induced recruitment of NKG2D to GM1-rich membrane domains at the human NK cell immune synapse.
NKG2D is an activating receptor expressed on all human NK cells and a subset of T cells. In cytolytic conjugates between NK cells and target cells expressing its ligand MHC class I chain-related gene A, NKG2D accumulates at the immunological synapse with GM1-rich microdomains. Furthermore, NKG2D is specifically recruited to detergent-resistant membrane fractions upon ligation. However, in the presence of a strong inhibitory stimulus, NKG2D-mediated cytotoxicity can be intercepted, and recruitment of NKG2D to the immunological synapse and detergent-resistant membrane fractions is blocked. Also, downstream phosphorylation of Vav-1 triggered by NKG2D ligation is circumvented by coengaging inhibitory receptors. Thus, we propose that one way in which inhibitory signaling can control NKG2D-mediated activation is by blocking its recruitment to GM1-rich membrane domains. The accumulation of activating NK cell receptors in GM1-rich microdomains may provide the necessary platform from which stimulatory signals can proceed.
Endt
Johanna
J
Institute for Immunology, University Heidelberg, Im Neuenheimer Feld 305, Heidelberg, Germany.
McCann
Fiona E
FE
Almeida
Catarina R
CR
Urlaub
Doris
D
Leung
Rufina
R
Pende
Daniela
D
Davis
Daniel M
DM
Watzl
Carsten
C
D000199:Actins / Q000378:metabolism; D002478:Cells, Cultured; D005677:G(M1) Ganglioside / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology*; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010766:Phosphorylation; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011971:Receptors, Immunologic / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054342:Receptors, KIR2DL1; D055607:Receptors, Natural Killer Cell
D000199:Actins; C093100:KIR2DL1 protein, human; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D051567:Proto-Oncogene Proteins c-vav; D011971:Receptors, Immunologic; D054342:Receptors, KIR2DL1; D055607:Receptors, Natural Killer Cell; C496618:VAV1 protein, human; D005677:G(M1) Ganglioside