B7-H4 Modulates Regulatory CD4+ T Cell Induction and Function via Ligation of a Semaphorin 3a/Plexin A4/Neuropilin-1 Complex.

The potent immune regulatory function of an agonistic B7-H4-Ig fusion protein (B7-H4Ig) has been demonstrated in multiple experimental autoimmune models; however, the identity of a functional B7-H4 receptor remained unknown. The biological activity of B7-H4 is associated with decreased inflammatory CD4+ T cell responses as supported by a correlation between B7-H4-expressing tumor-associated macrophages and Foxp3+ T cells within the tumor microenvironment. Recent data indicate that members of the semaphorin (Sema)/plexin/neuropilin (Nrp) family of proteins both positively and negatively modulate immune cell function. In this study, we show that B7-H4 binds the soluble Sema family member Sema3a. Additionally, B7-H4Ig-induced inhibition of inflammatory CD4+ T cell responses is lost in both Sema3a functional mutant mice and mice lacking Nrp-1 expression in Foxp3+ T cells. These findings indicate that B7-H4Ig binds to Sema3a, which acts as a functional bridge to stimulate an Nrp-1/Plexin A4 heterodimer to form a functional immunoregulatory receptor complex resulting in increased levels of phosphorylated PTEN and enhanced regulatory CD4+ T cell number and function.

Overexpression of the dominant-negative form of interferon regulatory factor 1 in oligodendrocytes protects against experimental autoimmune encephalomyelitis.

Interferon regulatory factor 1 (IRF-1) is a transcription factor that has been implicated in the pathogenesis of the human autoimmune demyelinating disease multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). The goal of the present study was to directly examine the role of IRF-1 in oligodendrocyte injury and inflammatory demyelination. For the purpose of this study, we generated a transgenic mouse line (CNP/dnIRF-1) that overexpresses the dominant-negative form of IRF-1 (dnIRF1) specifically in oligodendrocytes. CNP/dnIRF-1 mice exhibited no phenotypic abnormalities but displayed suppressed IRF-1 signaling in oligodendrocytes. The major finding of our study was that the CNP/dnIRF-1 mice, compared with the wild-type mice, were protected against EAE, a phenomenon associated with significant reduction of inflammatory demyelination and with oligodendrocyte and axonal preservation. The observed protection was related to suppressed IRF-1 signaling and impaired expression of immune and proapoptotic genes in oligodendrocytes. No significant differences in the peripheral immune responses between the wild-type and the CNP/dnIRF-1 mice were identified throughout the experiments. This study indicates that IRF-1 plays a critical role in the pathogenesis of EAE by mediating oligodendrocyte response to inflammation and injury. It also suggests that oligodendrocytes are actively involved in the neuroimmune network, and that exploring oligodendrocyte-related pathogenic mechanisms, in addition to the conventional immune-based ones, may have important therapeutic implications in MS.

IRF-1 signaling in central nervous system glial cells regulates inflammatory demyelination.

The present study provides evidence that interferon regulatory factor 1 (IRF-1) signaling in glial cells is involved in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Using a bone marrow chimera model of EAE, we demonstrated that CNS IRF-1 regulates inflammatory demyelination and disease severity independently of the peripheral immune cells. In addition, we identified Caspase 1, a pro-inflammatory and pro-apoptotic molecule, as an important transcriptional target of IRF-1. The findings of our study indicate that IRF-1 signaling in glial cells serves as a final common pathway of inflammatory demyelination and may have important clinical implications in MS.

Central nervous system expression of interferon regulatory factor 1 regulates experimental autoimmune encephalomyelitis.

Interferon regulatory factor 1 (IRF-1) is a transcription factor that has been implicated in the disease mechanisms of experimental autoimmune encephalomyelitis (EAE). In this study, we examined the role of central nervous system (CNS) expression of IRF-1 in the natural course of EAE. In an effort to dissect the CNS effects from the peripheral immune effects of IRF-1, we generated bone marrow chimera mice that differentially expressed IRF-1 in the CNS and in the immune system. We found that mice lacking IRF-1 in the CNS developed significantly milder clinical symptoms and shorter disease duration compared to those with wild-type background. Based on these results, we concluded that the CNS expression of IRF-1 regulates the disease process in EAE. Our findings are relevant to the inflammatory mechanisms involved in multiple sclerosis and may provide a basis for development of novel therapeutic targets of the disease.