Research ArticleMultiple Sclerosis

In Active Relapsing-Remitting Multiple Sclerosis, Effector T Cell Resistance to Adaptive Tregs Involves IL-6–Mediated Signaling

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Science Translational Medicine  30 Jan 2013:
Vol. 5, Issue 170, pp. 170ra15
DOI: 10.1126/scitranslmed.3004970

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Patients with multiple sclerosis (MS) manifest demyelination and neurodegeneration mediated in part by CD4+ T cells that have escaped regulation. Resistance of pathogenic effector T cells (Teffs) to suppression by regulatory T cells (Tregs) has been demonstrated in several autoimmune diseases. Although impairment in Treg number and function has been observed in relapsing-remitting MS (RRMS), Teff resistance has not been well studied in this disease. To determine whether Teff resistance contributes to failed tolerance in RRMS, we performed Treg suppression assays with Teffs from either RRMS patients not on immunomodulatory therapy or healthy individuals. Teff resistance was present in the Teffs of RRMS patients with active disease but not from patients with inactive disease. Interleukin-6 (IL-6) and phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) promote Teff resistance to Tregs, and we found an increase in IL-6 receptor α (IL-6Rα) expression and elevated IL-6 signaling as measured by pSTAT3 in our RRMS subjects. Further, the impaired suppression in RRMS subjects correlated with an increase in IL-6Rα surface expression on CD4+ T cells and an increase in pSTAT3 in response to IL-6. To address whether the enhanced pSTAT3 contributed to Teff resistance in active RRMS patients, we blocked STAT3 phosphorylation and found that impaired suppression was reversed. Therefore, enhanced IL-6R signaling through pSTAT3, in some cases through increased IL-6Rα expression, contributed to Teff resistance in active RRMS. These markers may aid in determining disease activity and responsiveness to immunomodulatory therapies in RRMS.

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