Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis
Humblet-Baron, Stephanie × Sather, Blythe Anover, Stephanie Becker-Herman, Shirly Kasprowicz, Debora J Khim, Socheath Nguyen, Thuc Hudkins-Loya, Kelly Alpers, Charles E Ziegler, Steve F Ochs, Hans Torgerson, Troy Campbell, Daniel J Rawlings, David J #
American Society for Clinical Investigation
Journal of Clinical Investigation vol:117 issue:2 pages:407-418
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 autoinimune 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.