101. Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects.
- Author
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Paccani SR, Boncristiano M, Patrussi L, Ulivieri C, Wack A, Valensin S, Hirst TR, Amedei A, Del Prete G, Telford JL, D'Elios MM, and Baldari CT
- Subjects
- CD3 Complex metabolism, Calcium Signaling, Common Variable Immunodeficiency immunology, DNA, Complementary genetics, G(M1) Ganglioside metabolism, Gene Expression, Humans, In Vitro Techniques, Leukocyte Common Antigens genetics, Membrane Microdomains metabolism, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins c-fyn, Proto-Oncogene Proteins c-vav, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Antigen, T-Cell metabolism, ZAP-70 Protein-Tyrosine Kinase, src-Family Kinases genetics, Actins metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Common Variable Immunodeficiency genetics, Common Variable Immunodeficiency metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
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 CD3zeta 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 co-engagement. 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.
- Published
- 2005
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