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
Stephanie Humblet-Baron, Blythe Sather, Stephanie Anover, Shirly Becker-Herman, Debora J. Kasprowicz, Socheath Khim, Thuc Nguyen, Kelly Hudkins-Loya, Charles E. Alpers, Steve F. Ziegler, Hans Ochs, Troy Torgerson, Daniel J. Campbell, David J. Rawlings
Figure 1
WT Tregs are expanded in a WAS patient following reversion of a pathogenic mutation.
Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)