Defective regulatory and effector T cell functions in patients with FOXP3 mutations.
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.
Bacchetta
Rosa
R
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy.
Passerini
Laura
L
Gambineri
Eleonora
E
Dai
Minyue
M
Allan
Sarah E
SE
Perroni
Lucia
L
Dagna-Bricarelli
Franca
F
Sartirana
Claudia
C
Matthes-Martin
Susanne
S
Lawitschka
Anita
A
Azzari
Chiara
C
Ziegler
Steven F
SF
Levings
Megan K
MK
Roncarolo
Maria Grazia
MG
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology*; D011401:Promoter Regions, Genetic; D011504:Protein-Losing Enteropathies / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015415:Biomarkers; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2