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

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BlankJournal of Leukocyte Biology, doi:10.1189/jlb.0410197

Received for publication April 8, 2010.

Revised June 24, 2010.

Accepted for publication July 20, 2010.

The Wiskott-Aldrich syndrome protein regulates CTL cytotoxicity and is required

for efficient killing of B cell lymphoma targets

De Meester , Ronan Calvez , Salvatore Valitutti , and Loïc Dupr é@

INSERM, U563, and Université Toulouse III -Sabatier, Centre de

Physiopathologie de Toulouse Purpan, Toulouse, France

To whom correspondence should be addressed. E-mail: loic.dupre@... .

Abstract

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-(gamma), and TNF-(alpha)) 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.