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Defective regulatory and effector T cell functions in patients with FOXP3 mutations
Authors:Bacchetta Rosa  Passerini Laura  Gambineri Eleonora  Dai Minyue  Allan Sarah E  Perroni Lucia  Dagna-Bricarelli Franca  Sartirana Claudia  Matthes-Martin Susanne  Lawitschka Anita  Azzari Chiara  Ziegler Steven F  Levings Megan K  Roncarolo Maria Grazia
Affiliation:San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
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.
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