Location: Diet, Genomics and Immunology Lab
Title: Critical requirement for the Wiskott-Aldrich syndrome protein in Th2 effector function Authors
|Morales-Tirado, Vanessa - U OF ROCHESTER, NY|
|Sojka, Dorothy - U OF ROCHESTER|
|Katzman, Shoshana -|
|Lazarski, C -|
|Finkelman, L -|
|Fowell, Deborah -|
Submitted to: Blood
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 13, 2009
Publication Date: April 29, 2010
Citation: Morales-Tirado, V., Sojka, D.K., Katzman, S.D., Lazarski, C.A., Finkelman, L.D., Urban Jr, J.F., Fowell, D.J. 2010. Critical requirement for the Wiskott-Aldrich syndrome protein in Th2 effector function. Blood. 115(17):3498-3507. Interpretive Summary: Wiskott-Aldrich syndrome is a rare X-linked recessive disease in humans that is characterized by functional defects in both cellular and antibody=dependent immune function. Defects in Wiskott-Aldrich syndrome protein (WASp) are responsible for expression of the disease. Parasitic worm infections stimulate powerful immunity based on the production of distinct protein message molecules called interleukin (IL)-4 and IL-13. These interleukins also regulate intestinal immune function and physiology. A mouse model was developed that genetically blocked production of WASp and it was studied during parasitic infection to determine the role of WASp and its activity in the intestine. The studies showed that the clearance of the parasite, which is dependent on IL-4 activity, was blocked and that IL-4 gene expression was normal but protein synthesis was inhibited. This response indicated that WASp functions at the intestinal level and suggests that its role in regulating calcium channels and uncoupling IL-4 protein production were involved in the mechanism of action. This work will be of interest to those who study regulation of immune expression, but also to nutritionists and clinicians interested in regulators of intestinal function, host immunity, and nutrient absorption.
Technical Abstract: The Wiskott-Aldrich syndrome protein (WASp) regulates actin polymerization via activation of Arp2/3 and plays a role in the dynamics of the immunological synapse. How these events influence subsequent gene expression and effector function is unclear. We studied the role of WASp in CD4+ T cell effector function by transfer of naïve WASp-deficient (WAS-/-) CD4+ T cells to wild-type (WT) T cell-deficient hosts. WAS-/- CD4+ T cells mediated protective Th1 responses in vivo, but were unable to support Th2 immunity to Nippostronglyus brasilensis or Leishmania major. WASp-induced signaling was not required for initial Th2 programming, but was required for Th2 effector function. WAS-/- CD4+ T cells up-regulated IL-4 and GATA3 mRNA and secreted IL-4 protein during the first 5 days of Th2 differentiation. In the absence of WASp, however, cytokine transcription was uncoupled from protein production in Th2-primed effectors. WAS-/- Th2s failed to produce IL-4 protein on re-stimulation despite elevated IL-4/GATA3 mRNA levels, demonstrating a post-transcriptional role for WASp in IL-4 production. Moreover, modulation of WASp expression in WT Th2 effector cells specifically blocked IL-4 but not IFN-gamma production from Th1 effectors. These studies highlight a selective requirement for WASp in Th2 effector function.