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The forkhead box transcription factor FoxP3 controls the development and function of CD4+CD25+ regulatory T (Treg) cell. FoxP3 modulates gene expression in Treg cells by multiple epigenetic mechanisms that are not clearly defined. We identified FoxP3 interacting proteins in human T cells by co-IP/MS. We discovered that FoxP3 interacted with linker histone H1.5 via the leucine zipper (LZ) domain. Two independent IPEX patient-derived single residue mutations in the LZ of FoxP3 both abrogated its interaction with H1.5. Functionally, FoxP3 and H1.5 cooperatively repressed IL-2 expression in human T cells; and silencing of H1.5 expression inhibited the ability of FoxP3 to suppress IL-2 expression. We show that FoxP3 specifically enhanced H1.5 association at the IL-2 promoter, but reduce its association at the CTLA4 promoter, correlated with higher or lower histone acetylation of the respective promoters. Finally, silencing of H1.5 expression in human Treg cells impaired the Treg function to suppress target T cells. We conclude that FoxP3 interacts with H1.5 to alter its binding to target genes to modulate their expression and to program Treg function.

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FoxP3 determines the development of CD4+CD25+ regulatory T (Treg) cells and represses IL-2 expression in Treg cells. However, FoxP3+ Treg cells support higher levels of HIV-1 replication than FoxP3-CD4+ T cells. We report that FoxP3 enhances HIV-1 LTR but inhibits IL-2 promoter activity. This FoxP3 activity is mapped at the C-terminal forkhead domain and inactivated by human IPEX mutations. FoxP3 enhances HIV-1 LTR via specific NFkappaB binding sequences in an NFkappaB-dependant fashion. FoxP3 also enhances a minimal promoter containing the NFkappaB sequences derived from LTR but not from the MHC promoter in T cells, but represses both the HIV-1 LTR and MHC promoter in 293T cells. Interestingly, FoxP3 does not alter NFkappaB nuclear translocation but enhances its binding to the HIV-1 promoter in T cells. Therefore, FoxP3 distinctively modulates T cell activation and HIV-1 replication in human T cells by modulating NFAT and NFkappaB activity, respectively.