Wiskott-Aldrich Syndrome Protein-Deficient Mice Reveal a Role for WASP in T but Not B Cell Activation

Abstract

The Wiskott-Aldrich syndrome (WAS) is a human X-linked immunodeficiency resulting from mutations in a gene (WASP) encoding a cytoplasmic protein implicated in regulating the actin cytoskeleton. To elucidate WASP function, we disrupted the WASP gene in mice by gene-targeted mutation. WASP-deficient mice showed apparently normal lymphocyte development, normal serum immunoglobulin levels, and the capacity to respond to both T-dependent and T-independent type II antigens. However, these mice did have decreased peripheral blood lymphocyte and platelet numbers and developed chronic colitis. Moreover, purified WASP-deficient T cells showed markedly impaired proliferation and antigen receptor cap formation in response to anti-CD3epsilon stimulation. Yet, purified WASP-deficient B cells showed normal responses to anti-Ig stimulation. We discuss the implications of our findings regarding WASP function in receptor signaling and cytoskeletal reorganization in T and B cells and compare the effects of WASP deficiency in mice and humans.

Impaired in vitro regulatory T cell function associated with Wiskott–Aldrich syndrome

“…Treg cell suppression function depends on TCR stimulation (40) and requires direct cell-cell interaction (41). WASp deficiency is associated with defective TCR-mediated activation and impaired formation of the immunological synapse (6)(7)(8)(9)(42)(43)(44), both of which may affect Treg cell suppression activity. Interestingly, the partial rescue of in vitro suppression defects by pre-activation of WASp-deficient Treg cells with IL-2, suggests that optimization of T cell activation may overcome the defect of WAS Treg cells.…”

“…Was -/Y and Was -/-(129S6/SvEvTac-Was tm1Sbs /J) (8) and control 129S6/SvEvTac mice were obtained from Jackson Laboratory and Taconic, respectively and maintained in sterile housing with sterile food and water. Mice were maintained and experiments performed according to NHGRI Animal Care and Use Committee guidelines.…”

“…The disorder is caused by mutations of WAS, the gene encoding the WAS protein, WASp, a key regulator of actin polymerization that is expressed in nonerythroid hematopoietic cells (2). T cells isolated from WASp-deficient mice and WAS patients show multiple defects including reduced TCR-induced proliferation and IL-2 production associated with impaired actin polymerization, defects which are likely to contribute to the immunodeficiency in WAS (6)(7)(8)(9).…”

Lentiviral vectors transcriptionally targeted to hematopoietic cells by WASP gene proximal promoter sequences

“…The biological activity of WASp in stem cell populations is witnessed by the apparent non-random distribution of X-inactivation in female carriers of a mutant WASP gene, 35 and the demonstration of homing and engraftment defects in mutant mice. 36 The widespread but hematopoietic-restricted expression profile of WASp is dictated by WASP gene regulatory elements which are therefore attractive for expression of many hematopoietic genes.…”

Functional correction of T cells derived from patients with the Wiskott–Aldrich syndrome (WAS) by transduction with an oncoretroviral vector encoding the WAS protein

“…Murine models of WASP deficiency have been developed, 24,25 and recent results in our laboratory have shown that the phenotype can be corrected by stem cell transplantation. 26 Further, we have shown that WASP-deficient mice have impaired defenses against mycobacterial infection and secondary influenza challenge (Strom T, Lang R, and Turner S, unpublished observations).…”