Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects

• Published in: Blood 2005-07, Vol.106 (2), p.626-634
• Main Authors: Paccani, Silvia Rossi, Boncristiano, Marianna, Patrussi, Laura, Ulivieri, Cristina, Wack, Andreas, Valensin, Silvia, Hirst, Tim R., Amedei, Amedeo, del Prete, Gianfranco, Telford, John L., D'Elios, Mario M., Baldari, Cosima T.
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Biological and medical sciences; Calcium Signaling; CD3 Complex - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; Common Variable Immunodeficiency - metabolism; DNA, Complementary - genetics; G(M1) Ganglioside - metabolism; Gene Expression; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; In Vitro Techniques; Leukocyte Common Antigens - genetics; Medical sciences; Membrane Microdomains - metabolism; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-fyn; Proto-Oncogene Proteins c-vav; Receptors, Antigen, T-Cell - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; src-Family Kinases - genetics; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; ZAP-70 Protein-Tyrosine Kinase
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-05-2051

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 CD3ζ 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)