Defective Regulatory and Effector T Cell Functions in Patients with FOXP3 Mutations

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2006 Jun 3

PMID 16741580

Citations 194

Authors

Rosa Bacchetta

Laura Passerini

Eleonora Gambineri

Minyue Dai

Sarah E Allan

Lucia Perroni

Franca Dagna-Bricarelli

Claudia Sartirana

Susanne Matthes-Martin

Anita Lawitschka

Chiara Azzari

Steven F Ziegler

Megan K Levings

Maria Grazia Roncarolo

Affiliations

Soon will be listed here.

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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