Foxp3 represses retroviral transcription by targeting both NF-kappaB and CREB pathways.
Forkhead box (Fox)/winged-helix transcription factors regulate multiple aspects of immune responsiveness and Foxp3 is recognized as an essential functional marker of regulatory T cells. Herein we describe downstream signaling pathways targeted by Foxp3 that may negatively impact retroviral pathogenesis. Overexpression of Foxp3 in HEK 293T and purified CD4+ T cells resulted in a dose-dependent and time-dependent decrease in basal levels of nuclear factor-kappaB (NF-kappaB) activation. Deletion of the carboxyl-terminal forkhead (FKH) domain, critical for nuclear localization and DNA-binding activity, abrogated the ability of Foxp3 to suppress NF-kappaB activity in HEK 293T cells, but not in Jurkat or primary human CD4+ T cells. We further demonstrate that Foxp3 suppressed the transcription of two human retroviral promoters (HIV-1 and human T cell lymphotropic virus type I [HTLV-I]) utilizing NF-kappaB-dependent and NF-kappaB-independent mechanisms. Examination of the latter identified the cAMP-responsive element binding protein (CREB) pathway as a target of Foxp3. Finally, comparison of the percent Foxp3+CD4+CD25+ T cells to the HTLV-I proviral load in HTLV-I-infected asymptomatic carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis suggested that high Foxp3 expression is associated with low proviral load and absence of disease. These results suggest an expanded role for Foxp3 in regulating NF-kappaB- and CREB-dependent cellular and viral gene expression.
Grant
Christian
C
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Oh
Unsong
U
Fugo
Kazunori
K
Takenouchi
Norihiro
N
Griffith
Caitlin
C
Yao
Karen
K
Newhook
Timothy E
TE
Ratner
Lee
L
Jacobson
Steven
S
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D050882:CREB-Binding Protein / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D018390:Gene Targeting; D006801:Humans; D019169:Jurkat Cells / Q000166:cytology / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012190:Retroviridae / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D012333:RNA, Messenger; D050882:CREB-Binding Protein; C494363:CREBBP protein, human