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Foxp3 represses retroviral transcription by targeting both NF-kappaB and CREB pathways

Christian Grant1, Unsong Oh, Kazunori Fugo

  • 1Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Plos Pathogens
|May 3, 2006
PubMed

Insights

Forkhead box P3 (Foxp3) suppresses immune responses by inhibiting nuclear factor-kappaB (NF-kappaB) and cAMP-responsive element binding protein (CREB) pathways. High Foxp3 expression correlates with lower retroviral load and reduced disease severity in HTLV-I infections.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Forkhead box (Fox)/winged-helix transcription factors, including Foxp3, are crucial regulators of immune responses.
  • Foxp3 is a key marker for regulatory T cells, which play a vital role in immune suppression.
  • Retroviral infections like HIV-1 and HTLV-I pose significant health challenges, and understanding their pathogenesis is critical.

Purpose of the Study:

  • To investigate the downstream signaling pathways regulated by Foxp3.
  • To determine the impact of Foxp3 on the activation of nuclear factor-kappaB (NF-kappaB).
  • To explore Foxp3's role in the pathogenesis of human retroviral infections, specifically HIV-1 and HTLV-I.

Main Methods:

  • Overexpression of Foxp3 in HEK 293T cells and primary CD4+ T cells.
  • Deletion of the forkhead (FKH) domain to assess its role in Foxp3 function.
  • Analysis of NF-kappaB activation and transcription of retroviral promoters (HIV-1, HTLV-I).
  • Investigation of the cAMP-responsive element binding protein (CREB) pathway.
  • Correlation of Foxp3+CD4+CD25+ T cell percentages with HTLV-I proviral load in infected individuals.

Main Results:

  • Foxp3 overexpression led to a dose- and time-dependent decrease in NF-kappaB activation.
  • The FKH domain of Foxp3 was essential for suppressing NF-kappaB activity in HEK 293T cells.
  • Foxp3 suppressed transcription of HIV-1 and HTLV-I promoters via both NF-kappaB-dependent and -independent pathways.
  • The CREB pathway was identified as a target of Foxp3's suppressive activity.
  • Higher Foxp3 expression was associated with lower HTLV-I proviral load and absence of associated disease.

Conclusions:

  • Foxp3 plays a significant role in negatively regulating NF-kappaB and CREB signaling pathways.
  • Foxp3 can inhibit the transcription of human retroviral promoters, suggesting a role in controlling viral replication.
  • These findings indicate an expanded role for Foxp3 in regulating cellular and viral gene expression, with implications for retroviral pathogenesis and disease progression.

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