The Journal of Experimental Medicine
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Published online February 12, 2007
doi:10.1084/jem.20061338
The Journal of Experimental Medicine, Vol. 204, No. 2, 381-391
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Maillard et al.
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ARTICLE

 The Wiskott-Aldrich syndrome protein is required for the function of CD4+CD25+Foxp3+ regulatory T cells

Michel H. Maillard1,5,7, Vinicius Cotta-de-Almeida1,5,8, Fuminao Takeshima1,5, Deanna D. Nguyen1,5, Pierre Michetti7, Cathryn Nagler2,3,5, Atul K. Bhan4,6, and Scott B. Snapper1,5

1 Gastrointestinal Unit, 2 Division of Rheumatology, 3 Allergy and Immunology, and 4 Immunopathology Unit and the Center for the Study of Inflammatory Bowel Diseases, Massachusetts General Hospital, Boston, MA 02114
5 Department of Medicine and 6 Department of Pathology, Harvard Medical School, Boston, MA 02115
7 Division of Gastroenterology and Hepatology, Department of Medicine, Lausanne University Hospital, 1005 Lausanne, Switzerland
8 Department of Ultrastructure and Cell Biology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 21040-360 Rio de Janeiro, Brazil

CORRESPONDENCE Scott B. Snapper: ssnapper{at}hms.harvard.edu

The Wiskott-Aldrich syndrome, a primary human immunodeficiency, results from defective expression of the hematopoietic-specific cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASP). Because CD4+CD25+Foxp3+ naturally occurring regulatory T (nTreg) cells control autoimmunity, we asked whether colitis in WASP knockout (WKO) mice is associated with aberrant development/function of nTreg cells. We show that WKO mice have decreased numbers of CD4+CD25+Foxp3+ nTreg cells in both the thymus and peripheral lymphoid organs. Moreover, we demonstrate that WKO nTreg cells are markedly defective in both their ability to ameliorate the colitis induced by the transfer of CD45RBhi T cells and in functional suppression assays in vitro. Compared with wild-type (WT) nTreg cells, WKO nTreg cells show significantly impaired homing to both mucosal (mesenteric) and peripheral sites upon adoptive transfer into WT recipient mice. Suppression defects may be independent of antigen receptor–mediated actin rearrangement because both WT and WKO nTreg cells remodeled their actin cytoskeleton inefficiently upon T cell receptor stimulation. Preincubation of WKO nTreg cells with exogenous interleukin (IL)-2, combined with antigen receptor–mediated activation, substantially rescues the suppression defects. WKO nTreg cells are also defective in the secretion of the immunomodulatory cytokine IL-10. Overall, our data reveal a critical role for WASP in nTreg cell function and implicate nTreg cell dysfunction in the autoimmunity associated with WASP deficiency.

Abbreviations used: CTLA-4, cytotoxic T lymphocyte–associated antigen 4; GITR, glucocorticoid-induced TNF receptor; IBD, inflammatory bowel disease; nTreg, naturally occurring regulatory T; TRITC, tetramethylrhodamine isothiocyanate; WASP, Wiskott-Aldrich syndrome protein; WKO, WASP knockout.

M.H. Maillard and V. Cotta-de-Almeida contributed equally to this work.


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