Defective regulatory and effector T cell functions in patients with FOXP3 mutations
Rosa Bacchetta, … , Megan K. Levings, Maria Grazia Roncarolo
Rosa Bacchetta, … , Megan K. Levings, Maria Grazia Roncarolo
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1713-1722. https://doi.org/10.1172/JCI25112.
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Research Article Immunology

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-γ 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

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

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Figure 4

Suppressive activity of patients’ CD4+ CD25high T cells.

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Suppressive activity of patients’ CD4+ ...
The ability of freshly isolated CD4+CD25high T cells of patient 2, patient 2bis, patient 3, and NDs to suppress either ND CD4+CD25– effector T cells or autologous CD4+CD25– effector T cells was assessed (in the case of NDs, effector and suppressor cells were derived from the same individuals). Responder cells were activated either in the presence of 50,000 irradiated (60 Gy) APCs plus soluble anti-CD3 mAb (1 μg/ml) (A) or with anti-CD3 plus anti-CD28 mAb–coated beads (B) (see Methods for details). CD4+CD25high T cells (Treg) were added to activated responder cells (R), and [3H]thymidine incorporation was measured after 72 hours. Percentages indicate inhibition of proliferation.