The Wiskott-Aldrich syndrome protein regulates CTL cytotoxicity and is required for efficient killing of B cell lymphoma targets

Journal of Leukocyte Biology

Salvatore Valitutti¹  Ronan Calvez¹  Julie De Meester¹  Loïc Dupré¹ 

[1] INSERM, U563, and Université Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, FranceINSERM, U563, and Université Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, FranceINSERM, U563, and Université Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France

关键词: cytotoxic T cells;    immunodeficiency diseases;    tumor immunity;   

DOI  :  10.1189/jlb.0410197

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

WAS is a primary immunodeficiency as a result of mutations in the gene encoding the WASP, a key actin regulator of hematopoietic cells. Whether killing defects in CD8+ CTLs contribute to WAS-associated immunodeficiency and susceptibility to tumor development remains to be explored. CTL lines from WAS patients, generated by repeated stimulation with SAg-loaded B-EBV, displayed reduced production of cytokines (IL-2, IFN-γ, and TNF-α) but almost normal proliferation upon SAg stimulation. Although WAS CTLs killed target B cells in a SAg dose-dependent manner, their efficiency was reduced, especially at a low SAg dose. The cytotoxic efficiency of WAS CTLs was particularly reduced against tumoral B cell lines. WAS CTLs expressed normal levels of lytic molecules and demonstrated efficient exocytosis upon target cell encounter. However, the lytic granules appeared not to fully polarize toward the center of the CTL/tumor target cell contact area. Importantly, the use of a gene therapy lentiviral vector was sufficient to restore efficient cytotoxic activity. Our study suggests that CTL dysfunction contributes to the development of hematological malignancies in WAS patients.

【 授权许可】

Unknown