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¹ San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy
² Vita-Salute San Raffaele University, 20132 Milan, Italy
³ Department of Pediatrics, University of Turin, 10126 Turin, Italy
⁴ Department of Pediatrics, University of Brescia, Spedali Civili, 25125 Brescia, Italy
⁵ Department of Pediatrics, St. George Hospital University Medical Center, 1100 2807 Beirut, Lebanon
⁶ SB Ankara Diskapi Children's Hospital, 06500 Ankara, Turkey
⁷ Human Genome Department, Istituto di Tecnologie Biomediche, CNR ITB, 20090 Segrate, Milan, Italy

CORRESPONDENCE Maria-Grazia Roncarolo: m.roncarolo{at}hsr.it

A large proportion of Wiskott-Aldrich syndrome (WAS) patients develop autoimmunity and allergy. CD4⁺CD25⁺FOXP3⁺ natural regulatory T (nTreg) cells play a key role in peripheral tolerance to prevent immune responses to self-antigens and allergens. Therefore, we investigated the effect of WAS protein (WASP) deficiency on the distribution and suppressor function of nTreg cells. In WAS^–/– mice, the steady-state distribution and phenotype of nTreg cells in the thymus and spleen were normal. However, WAS^–/– nTreg cells engrafted poorly in immunized mice, indicating perturbed homeostasis. Moreover, WAS^–/– nTreg cells failed to proliferate and to produce transforming growth factor ß upon T cell receptor (TCR)/CD28 triggering. WASP-dependent F-actin polarization to the site of TCR triggering might not be involved in WAS^–/– nTreg cell defects because this process was also inefficient in wild-type (WT) nTreg cells. Compared with WT nTreg cells, WAS^–/– nTreg cells showed reduced in vitro suppressor activity on both WT and WAS^–/– effector T cells. Similarly, peripheral nTreg cells were present at normal levels in WAS patients but failed to suppress proliferation of autologous and allogeneic CD4⁺ effector T cells in vitro. Thus, WASP appears to play an important role in the activation and suppressor function of nTreg cells, and a dysfunction or incorrect localization of nTreg cells may contribute to the development of autoimmunity in WAS patients.

L. Dupré's present address is INSERM U563, Purpan University Hospital, 31024 Toulouse Cedex 3, France.

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