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

Abstract

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 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 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-6Rα expression, contributed to T(eff) resistance in active RRMS. These markers may aid in determining disease activity and responsiveness to immunomodulatory therapies in RRMS.

TLR2 Stimulation Regulates the Balance between Regulatory T Cell and Th17 Function: A Novel Mechanism of Reduced Regulatory T Cell Function in Multiple Sclerosis

“…Neutralization of IL-6 also reversed TLR2-induced expression of IL-17 and IL-22 in human Tregs (10). In addition to its direct effects on Tregs, IL-6 can enhance the resistance of effector T cells to Treg-mediated inhibition in patients with MS (46,47). Our observation of greater production of IL-6 by Tregs upon We observed increased production and secretion of Th17-associated cytokines and increased STAT3 protein phosphorylation in CD4 + T cells and subpopulations of T cells from RRMS patients in response to TLR2.…”

“…Increased STAT3 signaling was observed in experimental CNS inflammatory diseases (16,57), with a critical role played by its expression in CD4 + T cells (16). In addition, STAT3 phosphorylation in PBMCs was correlated with disease activity (58) and in mediating resistance of effector T cells to Treg-mediated inhibition in MS (46). These data suggest that inhibition of IL-6/STAT3 signaling can be a rational therapeutic strategy in MS.…”

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

“…Treg dysfunction is implicated in RRMS pathogenesis (36)(37)(38)(39)(40)(41)(42)(43). Notably, DAC HYP has demonstrated robust clinical efficacy despite an overall ∼50% reduction in circulating Tregs.…”

B Cell Receptor Recognition of Glatiramer Acetate is Required for Efficacy through Antigen Presentation and Cytokine Production

“…IL-6 secreted from B lymphocytes has been implicated in EAE pathogenesis and CNS pathology in mice [60][61][62][63]. In MS, a role for IL-6 in pathogenesis has been reported, however the source and mechanism of action remains unclear [64][65][66][67][68][69][70][71]. Therefore, the observed reduction in patients with GA treatment may be a contributing factor to its efficacy.…”