TY - JOUR
T1 - Defective regulatory and effector T cell functions in patients with FOXP3 mutations
AU - Bacchetta, Rosa
AU - Passerini, Laura
AU - Gambineri, Eleonora
AU - Dai, Minyue
AU - Allan, Sarah E.
AU - Perroni, Lucia
AU - Dagna-Bricarelli, Franca
AU - Sartirana, Claudia
AU - Matthes-Martin, Susanne
AU - Lawitschka, Anita
AU - Azzari, Chiara
AU - Ziegler, Steven F.
AU - Levings, Megan K.
AU - Roncarolo, Maria Grazia
PY - 2006/6/1
Y1 - 2006/6/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI25112
DO - 10.1172/JCI25112
M3 - Article
C2 - 16741580
AN - SCOPUS:33745211931
VL - 116
SP - 1713
EP - 1722
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -