Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis.
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.
Humblet-Baron
Stephanie
S
Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
Sather
Blythe
B
Anover
Stephanie
S
Becker-Herman
Shirly
S
Kasprowicz
Debora J
DJ
Khim
Socheath
S
Nguyen
Thuc
T
Hudkins-Loya
Kelly
K
Alpers
Charles E
CE
Ziegler
Steve F
SF
Ochs
Hans
H
Torgerson
Troy
T
Campbell
Daniel J
DJ
Rawlings
David J
DJ
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*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C495767:WAS protein, human; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein