title: Defective regulatory and effector T cell functions in patients with FOXP3 mutations.
abstract: The autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is caused by mutations in the forkhead box protein P3 (FOXP3) gene. In the mouse model of FOXP3 deficiency, the lack of CD4+ CD25+ Tregs is responsible for lethal autoimmunity, indicating that FOXP3 is required for the differentiation of this Treg subset. We show that the number and phenotype of CD4+ CD25+ T cells from IPEX patients are comparable to those of normal donors. CD4+ CD25high T cells from IPEX patients who express FOXP3 protein suppressed the in vitro proliferation of effector T cells from normal donors, when activated by "weak" TCR stimuli. In contrast, the suppressive function of CD4+ CD25high T cells from IPEX patients who do not express FOXP3 protein was profoundly impaired. Importantly, CD4+ CD25high T cells from either FOXP3+ or FOXP3- IPEX patients showed altered suppression toward autologous effector T cells. Interestingly, IL-2 and IFN-gamma production by PBMCs from IPEX patients was significantly decreased. These findings indicate that FOXP3 mutations in IPEX patients result in heterogeneous biological abnormalities, leading not necessarily to a lack of differentiation of CD4+ CD25high Tregs but rather to a dysfunction in these cells and in effector T cells.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
authors.forename: Laura
authors.initials: L
authors.lastname: Passerini
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gambineri
authors.forename: Minyue
authors.initials: M
authors.lastname: Dai
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Allan
authors.forename: Lucia
authors.initials: L
authors.lastname: Perroni
authors.forename: Franca
authors.initials: F
authors.lastname: Dagna-Bricarelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Sartirana
authors.forename: Susanne
authors.initials: S
authors.lastname: Matthes-Martin
authors.forename: Anita
authors.initials: A
authors.lastname: Lawitschka
authors.forename: Chiara
authors.initials: C
authors.lastname: Azzari
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
authors.forename: Megan K
authors.initials: MK
authors.lastname: Levings
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology*; D011401:Promoter Regions, Genetic; D011504:Protein-Losing Enteropathies / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2