Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 2484K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Maillard, M. H. Articles by Snapper, S. B. Search for Related Content PubMed PubMed Citation Articles by Maillard, M. H. Articles by Snapper, S. B. Related Collections Related Article Social Bookmarking                            What's this?

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 CD45RB^hi 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.

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

WASP regulates suppressor activity of human and murine CD4⁺CD25⁺FOXP3⁺ natural regulatory T cells

Francesco Marangoni, Sara Trifari, Samantha Scaramuzza, Cristina Panaroni, Silvana Martino, Luigi D. Notarangelo, Zeina Baz, Ayse Metin, Federica Cattaneo, Anna Villa, Alessandro Aiuti, Manuela Battaglia, Maria-Grazia Roncarolo, and Loïc Dupré
J. Exp. Med. 2007 204: 369-380. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

• Bosticardo, M., Marangoni, F., Aiuti, A., Villa, A., Grazia Roncarolo, M. (2009). Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood 113: 6288-6295 [Abstract] [Full Text]  
• Astrakhan, A., Ochs, H. D., Rawlings, D. J. (2009). Wiskott-Aldrich Syndrome Protein Is Required for Homeostasis and Function of Invariant NKT Cells. J. Immunol. 182: 7370-7380 [Abstract] [Full Text]  
• Westerberg, L. S., de la Fuente, M. A., Wermeling, F., Ochs, H. D., Karlsson, M. C. I., Snapper, S. B., Notarangelo, L. D. (2008). WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function. Blood 112: 4139-4147 [Abstract] [Full Text]  
• Pulecio, J., Tagliani, E., Scholer, A., Prete, F., Fetler, L., Burrone, O. R., Benvenuti, F. (2008). Expression of Wiskott-Aldrich Syndrome Protein in Dendritic Cells Regulates Synapse Formation and Activation of Naive CD8+ T Cells. J. Immunol. 181: 1135-1142 [Abstract] [Full Text]  
• Ozsahin, H., Cavazzana-Calvo, M., Notarangelo, L. D., Schulz, A., Thrasher, A. J., Mazzolari, E., Slatter, M. A., Le Deist, F., Blanche, S., Veys, P., Fasth, A., Bredius, R., Sedlacek, P., Wulffraat, N., Ortega, J., Heilmann, C., O'Meara, A., Wachowiak, J., Kalwak, K., Matthes-Martin, S., Gungor, T., Ikinciogullari, A., Landais, P., Cant, A. J., Friedrich, W., Fischer, A. (2008). Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation. Blood 111: 439-445 [Abstract] [Full Text]  
• Bouma, G., Burns, S., Thrasher, A. J. (2007). Impaired T-cell priming in vivo resulting from dysfunction of WASp-deficient dendritic cells. Blood 110: 4278-4284 [Abstract] [Full Text]  
• Tsuboi, S., Meerloo, J. (2007). Wiskott-Aldrich Syndrome Protein Is a Key Regulator of the Phagocytic Cup Formation in Macrophages. J. Biol. Chem. 282: 34194-34203 [Abstract] [Full Text]  
• Cotta-de-Almeida, V., Westerberg, L., Maillard, M. H., Onaldi, D., Wachtel, H., Meelu, P., Chung, U.-i., Xavier, R., Alt, F. W., Snapper, S. B. (2007). Wiskott Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development. Proc. Natl. Acad. Sci. USA 104: 15424-15429 [Abstract] [Full Text]  
• Eisenmann, K. M., West, R. A., Hildebrand, D., Kitchen, S. M., Peng, J., Sigler, R., Zhang, J., Siminovitch, K. A., Alberts, A. S. (2007). T Cell Responses in Mammalian Diaphanous-related Formin mDia1 Knock-out Mice. J. Biol. Chem. 282: 25152-25158 [Abstract] [Full Text]  
• Marangoni, F., Trifari, S., Scaramuzza, S., Panaroni, C., Martino, S., Notarangelo, L. D., Baz, Z., Metin, A., Cattaneo, F., Villa, A., Aiuti, A., Battaglia, M., Roncarolo, M.-G., Dupre, L. (2007). WASP regulates suppressor activity of human and murine CD4+CD25+FOXP3+ natural regulatory T cells. JEM 204: 369-380 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS