WIP is critical for T cell responsiveness to IL-2.
The Wiskott-Aldrich syndrome (WAS) interacting protein (WIP) stabilizes the WAS protein (WASP), the product of the gene mutated in WAS. WIP-deficient T cells have low WASP levels, limiting the usefulness of WIP KO mice in defining the role of WIP in T cell function. To define this role, we compared WIP/WASP double KO (DKO) mice to WASP KO mice on DO11.10 background. T cell development was normal in both strains, but peripheral T cell numbers were significantly decreased in DKO mice. WASP KO T cells proliferated and secreted IL-2 normally in response to OVA peptide (OVAp). In contrast, T cells from DKO mice proliferated poorly in response to OVAp in vitro, and cutaneous hapten hypersensitivity was deficient in these mice. DKO T cells up-regulated CD25 expression and secreted normal amounts of IL-2 after antigen stimulation, but had defective response to IL-2, evidenced by failure to further up-regulate CD25 expression, phosphorylate STAT5, and induce expression of STAT5-dependent genes. DKO, but not WASP KO, T cells had a disrupted subcortical actin cytoskeleton and impaired actin polymerization after T cell antigen receptor (TCR) ligation. These results indicate that WIP is essential for IL-2 signaling and responsiveness in T cells, possibly because of its critical role in TCR-triggered actin cytoskeletal reorganization.
Division of Immunology, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Severine
S
Le Bras
Michel
M
Massaad
Suresh
S
Koduru
Lalit
L
Kumar
Michiko K
MK
Oyoshi
John
J
Hartwig
Raif S
RS
Geha
D000199:Actins / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D000941:Antigens / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000276:immunology / Q000648:ultrastructure; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000254:growth & development / Q000276:immunology; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000502:physiology
D000199:Actins; D000941:Antigens; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; C495768:Was protein, mouse; C491671:Waspip protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein