Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia.
Regulatory T cells are believed to control the development and progression of autoimmunity by suppressing autoreactive T cells. Decreased numbers of CD4(+)CD25(+) FOXP3(+) T cells (Tregs) are associated with impaired immune homeostasis and development of autoimmune diseases. The transcription factors FOXP3 and NFAT1 have key roles in regulatory T-cell development and function. We show that Tregs are decreased at presentation in almost all patients with aplastic anemia; FOXP3 protein and mRNA levels also are significantly lower in patients with aplastic anemia and NFAT1 protein levels are decreased or absent. Transfection of FOXP3-deficient CD4(+)CD25(+) T cells from patients with a plasmid encoding wild-type NFAT1 resulted in increased FOXP3 expression in these cells. By NFAT1 knockdown in CD4(+)CD25(+) T cells, FOXP3 expression was decreased when NFAT1 expression was decreased. Our findings indicate that decreased NFAT1 could explain low FOXP3 expression and diminished Treg frequency in aplastic anemia. Treg defects are now implicated in autoimmune marrow failure.
Solomou
Elena E
EE
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. solomoue@nhlbi.nih.gov
Rezvani
Katayoun
K
Mielke
Stephan
S
Malide
Daniela
D
Keyvanfar
Keyvan
K
Visconte
Valeria
V
Kajigaya
Sachiko
S
Barrett
A John
AJ
Young
Neal S
NS
D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014162:Transfection
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human