title: WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells.
abstract: 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 beta 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.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marangoni
authors.forename: Sara
authors.initials: S
authors.lastname: Trifari
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.forename: Cristina
authors.initials: C
authors.lastname: Panaroni
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Zeina
authors.initials: Z
authors.lastname: Baz
authors.forename: Ayse
authors.initials: A
authors.lastname: Metin
authors.forename: Federica
authors.initials: F
authors.lastname: Cattaneo
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Manuela
authors.initials: M
authors.lastname: Battaglia
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: Loïc
authors.initials: L
authors.lastname: Dupré
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016130:Immunophenotyping; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein