Proinflammatory cytokines regulate antigen-independent T-cell Activation by two separate calcium-signaling pathways in multiple sclerosis patients

Central nervous system (CNS) lesions typical of multiple sclerosis (MS) are characterized by demyelinating inflammatory infiltrates that contain few CNS antigen‐specific autoreactive T cells and a multitude of pathogenic non‐antigen‐specific mononuclear cells. Here, we report that in patients with MS the combined action of interferon‐γ (IFNγ), tumor necrosis factor‐α (TNFα), interleukin (IL)‐2, and IL‐6 leads to the activation of most peripheral T cells (mainly CD4 memory) by promoting a persistent intracellular calcium increase via two independent signaling pathways. The activation of these pathways, one activated by IFNγ and the other by the combination TNFα/IL‐2/IL‐6, is independent from myelin antigens and precedes by 2 weeks phases of disease activity (eg, clinical relapses and/or appearance of gadolinium‐enhancing lesions on brain magnetic resonance imaging scans during 1 year of follow‐up). Our results indicate that an appropriate combination of the four cytokines, three with a proinflammatory profile and one necessary for T‐cell growth and differentiation, can activate in an antigen‐independent fashion most peripheral T cells from MS patients. This mechanism is likely to contribute to the recruitment of nonspecific lymphocytes into the cellular activation processes leading to CNS demyelination and may represent a major target for immune intervention in MS.