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 3

WASp–/– Tregs fail to control autoimmunity in sf mice.

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WASp–/– Tregs fail to control autoimmunity in sf mice. M...
Male Ly5.1 sf neonates (>3 days of age) were injected i.p. with 1 × 106 to 2 × 106 CD4+CD25+-enriched WT or WASp–/– Tregs (both Ly5.2), sacrificed at 30–45 days after cell transfer, and evaluated for levels of T cell activation and tissue inflammation. (A) WT Tregs but not WASp–/– Tregs prevent development of activated sf lymphocytes. Lymphocytes isolated from the spleen and lung parenchyma of recipient mice were stained for CD4, Ly5.1, CD44, and CD45RB. The relative percentage of activated CD44hiCD45RBlow T cells in each tissue is shown. All plots are gated on CD4+Ly5.1+ cells to identify recipient-derived cells, and donor cell source is indicated above each panel. Controls included age-matched, unmanipulated sf and WT animals. (B) Graph represents the percentage of CD44hiCD45RBlow-activated, recipient-derived cells (CD4+Ly5.1+) among all recipient animals. Each point represents data from 1 sf recipient of either WASp–/– (n = 5) or WT (n = 2) Tregs. (C) WT Tregs but not WASp–/– Tregs rescue sf mutant mice from development of autoimmune infiltration of major organs. Formalin-fixed liver and lung tissue from sf mice that received WT versus WASp–/– Tregs were paraffin embedded, sectioned, and stained with H&E to visualize tissue structure and inflammatory cell infiltration. Liver and lung sections from unmanipulated sf and WT mice are shown for comparison. Original magnification, ×10.