title: Defective inhibition of B-cell proliferation by Wiskott-Aldrich syndrome protein-deficient regulatory T cells.
abstract: Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency characterized by high incidence of autoantibody-mediated autoimmune complications. Such a feature has been associated with defective suppressor activity of WAS protein-deficient, naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T cells on responder T cells. However, it remains to be established whether the altered B-cell tolerance reported in WAS patients and Was knockout (WKO) mice is secondary to abnormalities in the direct suppression of B-cell function by nTreg cells or to impaired regulation of T-helper function. Because activated nTreg cells are known to induce granzyme B-mediated B-cell killing, we decided to evaluate the regulatory capabilities of WKO nTregs on B lymphocytes. We found that preactivated WKO nTreg cells failed to effectively suppress B-cell proliferation and that such a defect was associated with reduced killing of B cells and significantly decreased degranulation of granzyme B. Altogether, these results provide additional mechanistic insights into the loss of immune tolerance in WAS.
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, MD, USA.
authors.forename: Marsilio
authors.initials: M
authors.lastname: Adriani
authors.forename: Krysten A
authors.initials: KA
authors.lastname: Jones
authors.forename: Toru
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Martha R
authors.initials: MR
authors.lastname: Kirby
authors.forename: Christopher
authors.initials: C
authors.lastname: Silvin
authors.forename: Stacie M
authors.initials: SM
authors.lastname: Anderson
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D053804:Granzymes / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000502:physiology*; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D051316:Wiskott-Aldrich Syndrome Protein; D053804:Granzymes