Defective regulatory and effector T cell functions in patients with FOXP3 mutations

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

Research output: Contribution to journalArticle

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+CD25 high Tregs but rather to a dysfunction in these cells and in effector T cells.

Original languageEnglish
Pages (from-to)1713-1722
Number of pages10
JournalJournal of Clinical Investigation
Volume116
Issue number6
DOIs
Publication statusPublished - Jun 1 2006

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Regulatory T-Lymphocytes
T-Lymphocytes
Mutation
Tissue Donors
Forkhead Transcription Factors
Autoimmunity
Autoimmune Diseases
Interleukin-2
Proteins
Phenotype
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., ... Roncarolo, M. G. (2006). Defective regulatory and effector T cell functions in patients with FOXP3 mutations. Journal of Clinical Investigation, 116(6), 1713-1722. https://doi.org/10.1172/JCI25112

Defective regulatory and effector T cell functions in patients with FOXP3 mutations. / 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.

In: Journal of Clinical Investigation, Vol. 116, No. 6, 01.06.2006, p. 1713-1722.

Research output: Contribution to journalArticle

Bacchetta, R, Passerini, L, Gambineri, E, Dai, M, Allan, SE, Perroni, L, Dagna-Bricarelli, F, Sartirana, C, Matthes-Martin, S, Lawitschka, A, Azzari, C, Ziegler, SF, Levings, MK & Roncarolo, MG 2006, 'Defective regulatory and effector T cell functions in patients with FOXP3 mutations', Journal of Clinical Investigation, vol. 116, no. 6, pp. 1713-1722. https://doi.org/10.1172/JCI25112
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. / Defective regulatory and effector T cell functions in patients with FOXP3 mutations. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 6. pp. 1713-1722.
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