title: Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects.
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.
authors.affiliation: Department of Evolutionary Biology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Silvia Rossi
authors.initials: SR
authors.lastname: Paccani
authors.forename: Marianna
authors.initials: M
authors.lastname: Boncristiano
authors.forename: Laura
authors.initials: L
authors.lastname: Patrussi
authors.forename: Cristina
authors.initials: C
authors.lastname: Ulivieri
authors.forename: Andreas
authors.initials: A
authors.lastname: Wack
authors.forename: Silvia
authors.initials: S
authors.lastname: Valensin
authors.forename: Tim R
authors.initials: TR
authors.lastname: Hirst
authors.forename: Amedeo
authors.initials: A
authors.lastname: Amedei
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Del Prete
authors.forename: John L
authors.initials: JL
authors.lastname: Telford
authors.forename: Mario M
authors.initials: MM
authors.lastname: D'Elios
authors.forename: Cosima T
authors.initials: CT
authors.lastname: Baldari
mesh_terms: D000199:Actins / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D020013:Calcium Signaling; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D005677:G(M1) Ganglioside / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D017493:Leukocyte Common Antigens / Q000235:genetics; D021962:Membrane Microdomains / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D051567:Proto-Oncogene Proteins c-vav; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D000199:Actins; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C496618:VAV1 protein, human; D005677:G(M1) Ganglioside; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D019061:src-Family Kinases; D017493:Leukocyte Common Antigens