Between periods of disease remission, individuals with multiple sclerosis suffer distressing bouts of relapse and worsening of disease, eventually leading to a debilitating state. What determines the relapsing–remitting phases that characterize this devastating disease is a key unanswered question. Lawrence Steinman and colleagues now suggest that osteopontin could be a major player in triggering disease relapse, through its ability to promote the survival of autoreactive T cells.

Osteopontin is a pleiotropic cytokine that participates in a wide range of biological processes, such as bone remodelling, cancer and inflammation. Increased expression of osteopontin has been detected at sites of pathology in several autoimmune diseases, including in the brain lesions of patients with multiple sclerosis during disease relapse. This, together with the observation that mice deficient in osteopontin develop a milder form of experimental autoimmune encephalomyelitis (EAE; an animal model of multiple sclerosis) with fewer relapses, prompted the authors to assess whether osteopontin contributes to disease progression.

Using three models of multiple sclerosis, they showed that administration of recombinant osteopontin could indeed exacerbate disease. In osteopontin-deficient mice, a daily injection of osteopontin after the first phase of spontaneous remission of EAE triggered immediate relapse and led to severe fatal disease. Administration of osteopontin also worsened disease in wild-type mice with a relapsing–remitting model of EAE.

Because autoreactive T cells that infiltrate the central nervous system (CNS) are thought to be responsible for the pathology of EAE and because death of these cells has been associated with spontaneous remission, the authors assayed for T-cell death in CNS tissue sections from osteopontin-deficient and wild-type mice. They showed that osteopontin-deficient mice had more apoptotic cells in the CNS lesions than wild-type mice, indicating that osteopontin might support the survival of pathogenic T cells. To assess this further, they studied the effects of osteopontin on T cells in vitro. Osteopontin reduced cell death in cultures of wild-type activated T cells, and this was shown to be due to increased T-cell survival, as opposed to increased cell division.

So, how does osteopontin increase the survival of activated T cells? Treatment of T cells with osteopontin promoted activation of the pro-survival transcription factor NF-κB (nuclear factor-κB) while inhibiting activation of the pro-apoptotic transcription factor FOXO3A (forkhead box O3A). This effect was shown to be mediated by osteopontin-mediated phosphorylation of IκB kinase-β (IKKβ), which in turn phosphorylates both IκBα (inhibitor of NF-κB), leading to its degradation, and FOXO3A. Inhibition of the transcriptional activity of FOXO3A prevented expression of the pro-apoptotic factor BIM (BCL-2-interacting mediator of cell death), which is involved in activating the pro-apoptotic proteins BAK (BCL-2 antagonist/killer) and BAX (BCL-2-associated X protein). Finally, the anti-apoptotic effect of osteopontin was further illustrated by its ability to inhibit nuclear translocation of the mitochondrial protein AIF (apoptosis-inducing factor) — a feature of apoptotic cell death.

On the basis of these observations, the authors propose a model whereby the presence of osteopontin in the brain promotes disease progression, by protecting activated autoimmune T cells from cell death, which would otherwise provide an 'extra layer' of protection from severe autoimmunity. This role for osteopontin supports the idea that therapeutic targeting of this factor could restrain the progression of multiple sclerosis.