Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis
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
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
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Research Article Immunology

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

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

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Figure 2

WASp–/– mice develop high-titer autoantibodies, and WT Tregs expand and rescue transplanted WASp–/– mice from autoimmune colitis.

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WASp–/– mice develop high-titer autoantibodies, and WT Tregs expand and ...
Presence of IgG dsDNA autoantibodies in the serum of (A) 129SvEv (129sv) or (B) C57BL/6 (Black-6) WASp–/– mice versus age- and sex-matched WT controls or 25- to 38-week-old BWF1 mice (positive control). Antibody titers were assessed by ELISA (n = 3–6 animals for each strain/sex). 2°Ab control, background values obtained using secondary antibody alone. Error bars represent SD. (C) WASp expression within T and B cells (CD3 and B220, respectively) but not myeloid cells allows for a competitive advantage over time in lethally irradiated WASp–/– recipients (129SvEv strain) transplanted with a 1:3 mixture of WT to WASp–/– BM cells. Peripheral blood from 5 mice was serially analyzed by flow cytometry at the indicated times after transplant to determine the percentage of WASp+ T, B, or myeloid cells. (D) The selective advantage of WASp-expressing cells within the T cell compartment is most marked in the peripheral Treg subset. WASp–/– mice (129SvEv strain) were transplanted as in C, and WASp expression among the indicated T cell populations was evaluated 12 months after transplant. WASp+ myeloid cells remain at the same percentage as when originally transplanted (approximately 25%), indicating no selective advantage. Recipients of WT:WASp–/– mixed BM transplants did not develop fatal, radiation-induced colitis, which occurred in all recipients of WASp–/– BM (data not shown). DP, CD4+CD8+ thymocytes; PLN Tregs, peripheral lymph node Tregs.