P170 The immunomodulatory effect of type I interferon signaling in T cells during the onset of experimental autoimmune encephalomyelitis (EAE)

Abstract

Introduction Interferon beta (IFN β ) is used widely as first-line treatment for multiple sclerosis (MS). However, the role of endogenous versus exogenous IFN β remains enigmatic with often contradictory results. During experimental autoimmune encephalomyelitis (EAE), an induced animal model of MS, neuroantigen-specific T cells exist in the periphery before the clinical signs of the disease. Our objective is to study how IFN β signaling in peripheral T cells affects the outcome of EAE. Methods To investigate the effect of type I IFNs on T cells during EAE, transgenic mice, that express functional type I IFN receptor (IFNAR1) exclusively on T lymphocytes, were generated. Wild-type (WT), IFNAR1 knockout (IFNAR1 −/− ) and transgenic (TgIFNAR1 −/− T +/− ) mice were immunized with MOG 35-55 peptide, to induce EAE. Clinical score was monitored and cytokine production by T cells in the periphery and the CNS was measured using flow cytometry in early phase of EAE. Additionally, spinal cord sections were assessed for inflammation, demyelination and axonal damage. To determine significant differences in clinical scores between study groups, the Mann–Whitney U test was performed. Results Transgenic mice exhibited a delayed onset and a milder progression of acute phase of EAE, as compared to WT and IFNAR1 −/− mice. No significant differences were detected in the proliferative capacity and the frequency of IL-17, IFN γ - or IL-10 producing T cells in spleen and draining lymph nodes, in either case of mice on day 17 of EAE. Moreover, no cells were detected within the CNS of TgIFNAR1 −/− T +/− mice, which was in accordance with their clinical score. However, IL-17 and IFN γ producing CD4+ cells were present in the spinal cord of WT and IFNAR1 −/− mice. Spinal cord sections from all groups showed lesions characteristic of EAE, although TgIFNAR1 −/− T +/− mice showed lower extent of pathology compared to IFNAR1 −/− , but similar to that of WT mice, with a lower degree of inflammation and neuronal degeneration. Conclusion These results indicate a protective role of endogenously produced type I IFNs in EAE, when signaling is T cell restricted. This role cannot be attributed either to pro- or anti-inflammatory cytokine profile of T cells in the periphery. To explore this phenomenon, we study the immunological response in the periphery, at the pre-onset of EAE, when T effector cells are already present, highly inflammatory. Our future goal is to investigate the effect of IFN β treatment both on clinical outcome of EAE and activation of T cells in our transgenic mice and the correlation with the observed beneficial effect of endogenous IFN β .