Expansion of Autoreactive T Cells in Multiple Sclerosis Is Independent of Exogenous B7 Costimulation

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the myelinated central nervous system that is postulated to be induced by myelin-reactive CD4 T cells. T cell activation requires an antigen-specific signal through the TCR and a costimulatory signal, which can be mediated by B7–1 or B7–2 engagement of CD28. To directly examine the activation state of myelin-reactive T cells in MS, the costimulation requirements necessary to activate myelin basic protein (MBP) or tetanus toxoid (TT)-reactive CD4 T cells were compared between normal controls and MS patients. Peripheral blood T cells were stimulated with Chinese hamster ovary (CHO) cells transfected either with DRB1*1501/DRA0101 chains (t-DR2) alone, or in combination with, B7–1 or B7–2. In the absence of costimulation, T cells from normal subjects stimulated with the recall antigen TT p830–843 were induced to expand and proliferate, but stimulation with MBP p85–99 did not have this effect. In marked contrast, T cells from patients with MS stimulated with MBP p85–99 in the absence of B7–1 or B7–2 signals expanded and proliferated. Thus, MBP-reactive CD4 T cells in patients with MS are costimulation independent and have been previously activated in vivo. These experiments provide further direct evidence for a role of activated MBP-specific CD4 T cells in the pathogenesis of MS.