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The role of the MHC class II transactivator (CIITA) in Ag presentation by astrocytes and susceptibility to experimental autoimmune encephalomyelitis (EAE) was examined using CIITA-deficient mice and newly created transgenic mice that used the glial fibrillary acidic protein promoter to target CIITA expression in astrocytes. CIITA was required for class II expression on astrocytes. Like class II-deficient mice, CIITA-deficient mice were resistant to EAE by immunization with CNS autoantigen, although T cells from immunized CIITA-deficient, but not class II-deficient, mice proliferated and secreted Th1 cytokines. CIITA-deficient splenic APC presented encephalitogenic peptide to purified wild-type encephalitogenic CD4+ T cells, indicating that CIITA-independent mechanisms can be used for class II-restricted Ag presentation in lymphoid tissue. CIITA-deficient mice were also resistant to EAE by adoptive transfer of encephalitogenic class II-restricted CD4+ Th1 cells, indicating that CIITA-dependent class II expression was required for CNS Ag presentation. Despite constitutive CIITA-driven class II expression on astrocytes in vivo, glial fibrillary acidic protein-CIITA transgenic mice were no more susceptible to EAE than controls. CIITA-transfected astrocytes presented peptide Ag, but in contrast to IFN-γ-activated astrocytes, they could not process and present native Ag. CIITA-transfected astrocytes did not express cathepsin S without IFN-γ activation, indicating that CIITA does not regulate other elements that may be required for Ag processing by astrocytes. Although our results demonstrate that CIITA-directed class II expression is required for EAE induction, CIITA-directed class II expression by astrocytes does not appear to increase EAE susceptibility. These results do not support the role of astrocytes as APC for class II-restricted Ag presentation during the induction phase of EAE.

Staphylococcal enterotoxins (SEs) are one member of a unique group of molecules known as superantigens. They are potent T-celi activators and stimulate a large number of T cells bearing specific T-cell-receptor -chain variable regions. It has been proposed that superantigens may trigger autoimmune disorders by stimulation of autoreactive T cells with restricted -chain variable-chain usage. We investigated the effects of SEs B and A (SEB and SEA) on the reactvation of experimental allergic encephalomyelitis, an animal model for multiple sclerosis. We report that SEB can reinduce encephalitis multipl times in PL/J mice that had previously recovered from an acute episode. SEB was also able to induce encephalitis in mice previously immunized with myelin basic protein but did not show clinical signs of dLswe. In addition, it was observed that T cells from PL/J mice that Superantigens such as the staphylococcal enterotoxins (SEs) are among the most powerful T-cell activators known (1-3). Stimulation of T cells by the superantigens occurs first by engaging the class II major histocompatibility complex and then the complex binds to the T-cell receptor (TCR) in a (-chain variable-region (V(3)-specific manner (1, 4). The SEs B and A (SEB and SEA, respectively), employed in this study, have been shown to be specific for murine T cells bearing V(33, -7, and -8.1-8.3 and V(1, -3, -10, -11, and -12, respectively (5). The observation that these enterotoxins can activate T cells based on TCR V gene usage has led to the concept that these antigens may trigger autoimmune disorders (6-9).Experimental allergic encephalomyelitis (EAE) is an animal model of antigen-induced autoimmunity and has been widely studied to gain insight into the inflammatory demyelinating disease multiple sclerosis (MS) (10

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Malignant gliomas (MGs), lethal human central nervous system (CNS) neoplasms, contain tumor infiltrating lymphocytes (TIL). Although MHC class II molecules are frequently detected on MG cells, suggesting that they may be capable of antigen (Ag) presentation to CD4(+) T cells, deficiencies in CD4(+) T-cell activation are associated with these nonimmunogenic tumors. We evaluated regulation of the MHC class II transactivator (CIITA), the key intermediate that controls class II expression, in MG cells and tested whether MG cells could process native Ag. After interferon-gamma (IFN-gamma) stimulation, MG cells upregulated CIITA and class II molecules. IFN-gamma-inducible CIITA expression in MG cells, as well as primary human astrocytes, was directed by two CIITA promoters, pIV, the promoter for IFN-gamma-inducible CIITA expression in nonprofessional antigen-presenting cells (APC), and pIII, the promoter that directs constitutive CIITA expression in B cells. Both pIII and pIV directed CIITA transcription in vivo in MGs and ex vivo in IFN-gamma-activated primary MG cultures. We also demonstrate for the first time that MG cells can process native Ag for presentation to CD4(+) MHC class II-restricted Th1 cells, indicating that MG cells can serve as nonprofessional APC. CIITA may be a key target to modulate MHC class II expression, which could augment immunogenicity, Ag presentation, and CD4(+) T-cell activation in MG therapy.

IFN-τ, a novel type I IFN that possesses immunomodulatory properties, lacks toxicity normally associated with other type I IFNs. We examined the effects of oral IFN-τ alone and in combination with oral glatiramer acetate in experimental allergic encephalomyelitis (EAE). By comparison of oral administration of IFN-α, -β, and -τ to myelin basic protein-specific TCR-transgenic mice, we demonstrate these type I IFNs promote secretion of the Th2 cytokine IL-10 with similar efficiency. Whereas IFN-α and -β induced IFN-γ secretion, a Th1 cytokine, IFN-τ did not. Oral IFN-τ alone suppressed EAE. When suboptimal doses were administered orally in combination to wild-type mice, IFN-τ and glatiramer acetate had a synergistic beneficial effect in suppression of EAE. This combination was associated with TGF-β secretion and enhanced IL-10 production. Thus, IFN-τ is a potential candidate for use as a single agent or in combination therapy for multiple sclerosis.