Naturally occurring CD4+CD25+ regulatory T cells (Treg) exert an important role in mediating maternal tolerance to the fetus during pregnancy, and this effect might be regulated via maternal estrogen secretion. Although estrogen concentration in the pharmaceutical range has been shown to drive expansion of CD4+CD25+ Treg cells, little is known about how and through what mechanisms E2 within the physiological concentration range of pregnancy affects this expansion. Using in vivo and in vitro mouse models in these experiments, we observed that E2 at physiological doses not only expanded Treg cell in different tissues but also increased expression of the Foxp3 gene, a hallmark for CD4+CD25+ Treg cell function, and the IL-10 gene as well. Importantly, our results demonstrate that E2, at physiological doses, stimulated the conversion of CD4+CD25- T cells into CD4+CD25+ T cells which exhibited enhanced Foxp3 and IL-10 expression in vitro. Such converted CD4+CD25+ T cells had similar regulatory function as naturally occurring Treg cells, as demonstrated by their ability to suppress naïve T cell proliferation in a mixed lymphocyte reaction. We also found that the estrogen receptor (ER) exist in the CD4+CD25- T cells and the conversion of CD4+CD25- T cells into CD4+CD25+ T cells stimulated by E2 could be inhibited by ICI182,780, a specific inhibitor of ER(s). This supports that E2 may directly act on CD4+CD25- T cells via ER(s). We conclude that E2 is a potential physiological regulatory factor for the peripheral development of CD4+CD25+ Treg cells during the implantation period in mice.
The ICP34.5 protein of herpes simplex virus type 1 is a neurovirulence factor that plays critical roles in viral replication and anti-host responses. One of its functions is to recruit protein phosphatase 1 (PP1) that leads to the dephosphorylation of the ␣ subunit of translation initiation factor eIF2 (eIF2␣), which is inactivated by infection-induced phosphorylation. As PP1 is a protein phosphatase with a wide range of substrates, the question remains to be answered how ICP34.5 directs PP1 to specifically dephosphorylate eIF2␣. Here we report that ICP34.5 not only binds PP1 but also associates with eIF2␣ by in vitro and in vivo assays. The binding site of eIF2␣ is identified at amino acids 233-248 of ICP34.5, which falls in the highly homologous region with human gene growth arrest and DNA damage 34. The interaction between ICP34.5 and eIF2␣ is independent of the phosphorylation status of eIF2␣ at serine 51. Deletion mutation of this region results in the failure of dephosphorylation of eIF2␣ by PP1 and, consequently, interrupts viral protein synthesis and replication. Our data illustrated that the binding between viral protein ICP34.5 and the host eIF2␣ is crucial for the specific dephosphorylation of eIF2␣ by PP1. We propose that herpes simplex virus protein ICP34.5 bridges PP1 and eIF2␣ via their binding motifs and thereby facilitates the protein synthesis and viral replication.Viral infection can activate a series of host immune responses. One of the essential responses is the interruption of the viral protein synthesis, which is executed by doublestranded RNA-dependent protein kinase (PKR) (1). PKR is induced and activated upon viral infection and leads to the phosphorylation of the ␣ subunit of translation initiation factor eIF2 (eIF2␣) 2 at serine 51 (2). The phosphorylation of eIF2␣ globally inhibits the synthesis of viral proteins and cellular proteins (3), thus halting the viral replication.Many viruses have evolved strategies to counteract the antiviral response of PKR (4). For example, PKR activity can be inhibited by HIV-encoded Tar (5), hepatitis C virus NS5A (6), influenza virus NS1 (7), and so forth. In addition to affecting PKR activation as mentioned above, HSV-1 adopted mechanisms not only inhibiting PKR by Us11 (8) but also reversing the biochemical reaction catalyzed by PKR with its neurovirulent factor ICP34.5 (9).ICP34.5 is encoded by the ␥ 1 34.5 gene of HSV-1 and HSV-2. The HSV-1(F) ICP34.5 consists of 263 amino acids and can be divided into three domains: an amino-terminal domain, a linker region of ATP (Ala-Thr-Pro) repeats, and a carboxyl-terminal domain (9, 10). The function of the amino-terminal domain is implicated in the control of TBK1-mediated signaling (11) and also related to autophagy (12). The linker region, with a varying number of the Ala-Thr-Pro repeats, may affect the protein localization (13). The carboxyl-terminal domain is a stretch of 84 amino acids containing a consensus binding motif (R/KVXF) for protein phosphatase 1 (PP1) followed by an Ala-Arg-rich motif and i...
The ␥ 1 34.5 protein of herpes simplex viruses (HSV) is essential for viral pathogenesis, where it precludes translational arrest mediated by double-stranded-RNA-dependent protein kinase (PKR). Paradoxically, inhibition of PKR alone is not sufficient for HSV to exhibit viral virulence. Here we report that ␥ 1 34.5 inhibits TANK binding kinase 1 (TBK1) through its amino-terminal sequences, which facilitates viral replication and neuroinvasion. Compared to wild-type virus, the ␥ 1 34.5 mutant lacking the amino terminus induces stronger antiviral immunity. This parallels a defect of ␥ 1 34.5 for interacting with TBK1 and reducing phosphorylation of interferon (IFN) regulatory factor 3. This activity is independent of PKR. Although resistant to IFN treatment, the ␥ 1 34.5 amino-terminal deletion mutant replicates at an intermediate level between replication of wild-type virus and that of the ␥ 1 34.5 null mutant in TBK1 ؉/؉ cells. However, such impaired viral growth is not observed in TBK1 ؊/؊ cells, indicating that the interaction of ␥ 1 34.5 with TBK1 dictates HSV infection. Upon corneal infection, this mutant replicates transiently but barely invades the trigeminal ganglia or brain, which is a difference from wild-type virus and the ␥ 1 34.5 null mutant. Therefore, in addition to PKR, ␥ 1 34.5 negatively regulates TBK1, which contributes viral replication and spread in vivo.
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