Foxp3 Represses Retroviral Transcription by Targeting Both NF-κB and CREB Pathways

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Abstract
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-κB (NF-κB) 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-κB 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-κB-dependent and NF-κB-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-κB- and CREB-dependent cellular and viral gene expression. Over the past several years, mounting evidence has shown that immune tolerance in healthy individuals can be maintained by a population of T lymphocytes known as regulatory T cells (Tregs). As a component of this system, a protein known as Foxp3 has been shown to be absolutely required for the development and function of Tregs. While Foxp3 plays an important role in maintaining immune tolerance by blocking T cell proliferation and production of inflammatory proteins known as cytokines, little is known about the molecular mechanisms that are used by Foxp3 to accomplish these events. The present study expands our understanding of how Foxp3 maintains a check on inappropriate immune responses by demonstrating that Foxp3 can block activation of key inducible proteins such as nuclear factor κB (NF-κB) and cAMP-responsive element binding protein (CREB). Since NF-κB and CREB are integrally involved in controlling cell cycle progression, inflammatory cytokine production, and the replication of numerous viruses at the level of transcription, understanding the mechanisms by which Foxp3 functions to regulate cellular and viral gene expression may aid in the discovery of therapeutic approaches designed to rescue the expression and/or function of Foxp3, which have been found to be deficient in several autoimmune diseases and virus-induced disorders.