Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis.

نویسندگان

  • 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
چکیده

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.

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عنوان ژورنال:
  • The Journal of clinical investigation

دوره 117 2  شماره 

صفحات  -

تاریخ انتشار 2007