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Microenvironment produced by acute myeloid leukemia cells prevents T cell activation and proliferation by inhibition of NF-kappaB, c-Myc, and pRb pathways.
Buggins, A G; Milojkovic, D; Arno, M J; Lea, N C; Mufti, G J; Thomas, N S; Hirst, W J.
Afiliación
  • Buggins AG; Department of Haematological Medicine, Leukaemia Sciences, Guy's, King's and St. Thomas' School of Medicine, Rayne Institute, London, United Kingdom. andrea.buggins@kcl.ac.uk
J Immunol ; 167(10): 6021-30, 2001 Nov 15.
Article en En | MEDLINE | ID: mdl-11698483
ABSTRACT
Tumors produce a variety of immunosuppressive factors which can prevent the proliferation and maturation of a number of normal hemopoietic cell types. We have investigated whether primary acute myeloid leukemia (AML) cells have an effect on normal T cell function and signaling. Tumor cell supernatant (TSN) from AML cells inhibited T cell activation and Th1 cytokine production and also prevented activated T cells from entering the cell cycle. These effects occurred in the absence of AML cell-T cell contact. We have demonstrated that AML TSN contained none of the immunosuppressors described to date, namely gangliosides, nitric oxide, TGF-beta, IL-10, vascular endothelial growth factor, or PGs. Furthermore, IL-2 did not overcome the block, despite normal IL-2R expression. However, the effect was overcome by preincubation with inhibitors of protein secretion and abolished by trypsinization, indicating that the active substance includes one or more proteins. To determine the mechanism of inhibition, we have studied many of the major pathways involved in T cell activation and proliferation. We show that nuclear translocation of NFATc and NF-kappaB are markedly reduced in T cells activated in the presence of primary AML cells. In contrast, calcium mobilization and activation of other signal transduction pathways, namely extracellular signal-regulated kinase1/2, p38, and STAT5 were unaffected, but activation of c-Jun N-terminal kinase 1/2 was delayed. Phosphorylation of pRb by cyclin-dependent kinase 6/4-cyclin D and of p130 did not occur and c-Myc, cyclin D3, and p107 were not induced, consistent with cell cycle inhibition early during the transition from G(0) to G(1). Our data indicate that TSN generated by AML cells induces T cell immunosuppression and provides a mechanism by which the leukemic clone could evade T cell-mediated killing.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Activación de Linfocitos / Linfocitos T / Leucemia Mieloide / Escape del Tumor / Proteínas de Unión al ADN Límite: Humans Idioma: En Revista: J Immunol Año: 2001 Tipo del documento: Article País de afiliación: Reino Unido
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Activación de Linfocitos / Linfocitos T / Leucemia Mieloide / Escape del Tumor / Proteínas de Unión al ADN Límite: Humans Idioma: En Revista: J Immunol Año: 2001 Tipo del documento: Article País de afiliación: Reino Unido