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Blood, 15 July 2005, Vol. 106, No. 2, pp. 626-634. Prepublished online as a Blood First Edition Paper on April 7, 2005; DOI 10.1182/blood-2004-05-2051.
IMMUNOBIOLOGY Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defectsFrom the Department of Evolutionary Biology, University of Siena, Siena, Italy; Chiron Research Center, Siena, Italy; School of Molecular and Microbial Biosciences, The University of Sydney, Sydney, NSW, Australia; and the Department of Internal Medicine and Immunoallergology, University of Florence, Florence, Italy.
Common variable immunodeficiency (CVID) is a primary immune disorder characterized by impaired antibody production, which is in many instances secondary to defective T-cell function (T-CVID). We have previously identified a subset of patients with T-CVID characterized by defective T-cell receptor (TCR)-dependent protein tyrosine phosphorylation. In these patients, ZAP-70 fails to be recruited to the TCR as the result of impaired CD3
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
phosphorylation, which is, however, not dependent on defective Lck expression or activity. Here we show that neither Fyn nor CD45 is affected in these patients. On the other hand, T-CVID T cells show dramatic defects in the Vav/Rac pathway controlling F-actin dynamics. A significant deficiency in Vav protein was indeed observed; in 3 of 4 patients with T-CVID, it was associated with reduced VAV1 mRNA levels. The impairment in Vav expression correlated with defective F-actin reorganization in response to TCR/CD28 coengagement. Furthermore, TCR/CD28-dependent up-regulation of lipid rafts at the cell surface, which requires F-actin dynamics, was impaired in these patients. The actin cytoskeleton defect could be reversed by reconstitution of Vav1 expression in the patients' T cells. Results demonstrate an essential role of Vav in human T cells and strongly suggest Vav insufficiency in T-CVID. (Blood. 2005;106:626-634) 
