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

Effector T cells in patients with active RRMS can be resistant to immune tolerance through a mechanism involving IL-6R signaling. A Pocket of Resistance The human immune system is a well-oiled machine, primed to quickly and ruthlessly destroy unwanted invaders. However, the wrong stimulus could set immune cells down another path—attacking the very host they’re there to protect. Fortunately, built-in regulatory mechanisms, such as regulatory T cells (Tregs), prevent just such an attack. These cells can suppress the function of effector T cells (Teffs), but what happens when Teffs are resistant to Treg-mediated suppression? Schneider et al. now report that some Teffs are resistant to Tregs in patients with active relapsing-remitting multiple sclerosis (RRMS) and that this resistance is dependent on interleukin-6 (IL-6) signaling. Although Treg resistance has been reported in other autoimmune diseases, little has been known about whether and how it contributes to RRMS pathogenesis. The authors first demonstrated that Teffs from RRMS patients, but not healthy controls, were resistant to the suppressive effects of Tregs. Moreover, they noticed increased expression of IL-6 signaling molecules in active RRMS subjects. If they blocked the IL-6 pathway ex vivo (by blocking STAT3 phosphorylation), Teffs from RRMS patients were no longer resistant to Tregs. Therefore, the IL-6 signaling pathway may serve as a target for reversing pathogenesis in RRMS patients. 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.