title: The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells.
abstract: 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.
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Michel H
authors.initials: MH
authors.lastname: Maillard
authors.forename: Vinicius
authors.initials: V
authors.lastname: Cotta-de-Almeida
authors.forename: Fuminao
authors.initials: F
authors.lastname: Takeshima
authors.forename: Deanna D
authors.initials: DD
authors.lastname: Nguyen
authors.forename: Pierre
authors.initials: P
authors.lastname: Michetti
authors.forename: Cathryn
authors.initials: C
authors.lastname: Nagler
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D016753:Interleukin-10; D017493:Leukocyte Common Antigens