Complex regulation of human NKG2D-DAP10 cell surface expression: opposing roles of the γc cytokines and TGF-ß1.
Blood
; 118(11): 3019-27, 2011 Sep 15.
Article
en En
| MEDLINE
| ID: mdl-21816829
ABSTRACT
Natural killer (NK) cells help protect the host against viral infections and tumors. NKG2D is a vital activating receptor, also expressed on subsets of T cells, whose ligands are up-regulated by cells in stress. Ligation of NKG2D leads to phosphorylation of the associated DAP10 adaptor protein, thereby activating immune cells. Understanding how the expression of NKG2D-DAP10 is regulated has implications for immunotherapy. We show that IL-2 and TGF-ß1 oppositely regulate NKG2D-DAP10 expression by NK cells. IL-2 stimulation increases NKG2D surface expression despite a decrease in NKG2D mRNA levels. Stimulation with IL-2 results in a small increase of DAP10 mRNA and a large up-regulation of DAP10 protein synthesis, indicating that IL-2-mediated effects are mostly posttranscriptional. Newly synthesized DAP10 undergoes glycosylation that is required for DAP10 association with NKG2D and stabilization of NKG2D expression. TGF-ß1 has an opposite and dominant effect to IL-2. TGF-ß1 treatment decreases DAP10, as its presence inhibits the association of RNA polymerase II with the DAP10 promoter, but not NKG2D mRNA levels. This leads to the down-regulation of DAP10 expression and, as a consequence, NKG2D protein as well. Finally, we show that other γ(c) cytokines act similarly to IL-2 in up-regulating DAP10 expression and NKG2D-DAP10 surface expression.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Receptores Inmunológicos
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Membrana Celular
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Citocinas
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Factor de Crecimiento Transformador beta1
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Subfamilia K de Receptores Similares a Lectina de Células NK
Límite:
Humans
Idioma:
En
Revista:
Blood
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos