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

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 (T-effs) to suppression by regulatory T cells (T-regs) has been demonstrated in several autoimmune diseases. Although impairment in T-reg number and function has been observed in relapsing-remitting MS (RRMS), T-eff resistance has not been well studied in this disease. To determine whether T-eff resistance contributes to failed tolerance in RRMS, we performed T-reg suppression assays with T-effs from either RRMS patients not on immunomodulatory therapy or healthy individuals. T-eff resistance was present in the T-effs 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 T-eff resistance to T-regs, and we found an increase in IL-6 receptor alpha (IL-6R alpha) 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-6R alpha surface expression on CD4(+) T cells and an increase in pSTAT3 in response to IL-6. To address whether the enhanced pSTAT3 contributed to T-eff 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-6R alpha expression, contributed to T-eff resistance in active RRMS. These markers may aid in determining disease activity and responsiveness to immunomodulatory therapies in RRMS.