Chemokine unresponsiveness of chronic lymphocytic leukemia cells results from impaired endosomal recycling of Rap1 and is associated with a distinctive type of immunological anergy.
J Immunol
; 191(3): 1496-504, 2013 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-23804711
ABSTRACT
Trafficking of malignant lymphocytes is fundamental to the biology of chronic lymphocytic leukemia (CLL). Transendothelial migration (TEM) of normal lymphocytes into lymph nodes requires the chemokine-induced activation of Rap1 and αLß2 integrin. However, in most cases of CLL, Rap1 is refractory to chemokine stimulation, resulting in failed αLß2 activation and TEM unless α4ß1 is coexpressed. In this study, we show that the inability of CXCL12 to induce Rap1 GTP loading in CLL cells results from failure of Rap1-containing endosomes to translocate to the plasma membrane. Furthermore, failure of chemokine-induced Rap1 translocation/GTP loading was associated with a specific pattern of cellular IgD distribution resembling that observed in normal B cells anergized by DNA-based Ags. Anergic features and chemokine unresponsiveness could be simultaneously reversed by culturing CLL cells ex vivo, suggesting that these two features are coupled and driven by stimuli present in the in vivo microenvironment. Finally, we show that failure of Rap1 translocation/GTP loading is linked to defective activation of phospholipase D1 and its upstream activator Arf1. Taken together, our findings indicate that chemokine unresponsiveness in CLL lymphocytes results from failure of Arf1/phospholipase D1-mediated translocation of Rap1 to the plasma membrane for GTP loading and may be a specific feature of anergy induced by DNA Ags.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfolipase D
/
Leucemia Linfocítica Crônica de Células B
/
Anergia Clonal
/
Fator 1 de Ribosilação do ADP
/
Proteínas de Ligação a Telômeros
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Reino Unido