Endogenous Interferon-β-Inducible Gene Expression and Interferon-β-Treatment Are Associated with Reduced T Cell Responses to Myelin Basic Protein in Multiple Sclerosis

Autoreactive CD4(+) T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-beta is used for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels of interferon-beta-inducible genes with an increased expression of interleukin-10 and a milder disease course in untreated multiple sclerosis patients, whereas other studies reported an association with a poor response to treatment with interferon-beta. In the present study, we found that untreated multiple sclerosis patients with an increased expression of interferon-beta-inducible genes in peripheral blood mononuclear cells and interferon-beta-treated multiple sclerosis patients had decreased CD4(+) T-cell reactivity to the autoantigen myelin basic protein ex vivo. Interferon-beta-treated multiple sclerosis patients had increased IL10 and IL27 gene expression levels in monocytes in vivo. In vitro, neutralization of interleukin-10 and monocyte depletion increased CD4(+) T-cell reactivity to myelin basic protein while interleukin-10, in the presence or absence of monocytes, inhibited CD4(+) T-cell reactivity to myelin basic protein. Our findings suggest that spontaneous expression of interferon-beta-inducible genes in peripheral blood mononuclear cells from untreated multiple sclerosis patients and treatment with interferon-beta are associated with reduced myelin basic protein-induced T-cell responses. Reduced myelin basic protein-induced CD4(+) T-cell autoreactivity in interferon-beta-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10.