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 paradoxial observations. While WASp-deficient (WASp-/-) mice exibited 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+ Treg 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.