title: Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis.
abstract: Wiskott-Aldrich syndrome protein (WASp) is essential for optimal T cell activation. Patients with WAS exhibit both immunodeficiency and a marked susceptibility to systemic autoimmunity. We investigated whether alterations in Treg function might explain these paradoxical observations. While WASp-deficient (WASp(-/-)) mice exhibited normal thymic Treg generation, the competitive fitness of peripheral Tregs was severely compromised. The total percentage of forkhead box P3-positive (Foxp3(+)) Tregs among CD4(+) T cells was reduced, and WASp(-/-) Tregs were rapidly outcompeted by WASp(+) Tregs in vivo. These findings correlated with reduced expression of markers associated with self-antigen-driven peripheral Treg activation and homing to inflamed tissue. Consistent with these findings, WASp(-/-) Tregs showed a reduced ability to control aberrant T cell activation and autoimmune pathology in Foxp3(-/-)Scurfy (sf) mice. Finally, WASp(+) Tregs exhibited a marked selective advantage in vivo in a WAS patient with a spontaneous revertant mutation, indicating that altered Treg fitness likely explains the autoimmune features in human WAS.
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Humblet-Baron
authors.forename: Blythe
authors.initials: B
authors.lastname: Sather
authors.forename: Stephanie
authors.initials: S
authors.lastname: Anover
authors.forename: Shirly
authors.initials: S
authors.lastname: Becker-Herman
authors.forename: Debora J
authors.initials: DJ
authors.lastname: Kasprowicz
authors.forename: Socheath
authors.initials: S
authors.lastname: Khim
authors.forename: Thuc
authors.initials: T
authors.lastname: Nguyen
authors.forename: Kelly
authors.initials: K
authors.lastname: Hudkins-Loya
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.forename: Steve F
authors.initials: SF
authors.lastname: Ziegler
authors.forename: Hans
authors.initials: H
authors.lastname: Ochs
authors.forename: Troy
authors.initials: T
authors.lastname: Torgerson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Campbell
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D002454:Cell Differentiation; D005260:Female; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D006706:Homeostasis; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C495767:WAS protein, human; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein