Autoimmunity in Active Relapsing-Remitting Multiple Sclerosis

Regulatory T-Cells and Immune Tolerance in MS

Multiple sclerosis (MS) is a chronically progressive, neuroinflammatory autoimmune disease of the central nervous system (CNS). It is driven in part by CD4+ T-cells that escape normal regulation and attack myelin protein peptides.

CD4⁺ CD25⁺ regulatory T-cells (T_regs) are a subset of suppressor T-cells. Their job is to maintain peripheral immune tolerance by actively suppressing auto-aggressive T-cells. Patients with secondary progressive MS (SPMS) have normal T_reg function. But patients with relapsing-remitting MS (RRMS) have T_regs that don’t work properly. This loss of regulatory control allows pathogenic CD4 T-cells to infiltrate the CNS and drive neuroinflammation.

RRMS patients have both lower T_reg numbers and impaired T_reg function. Yet earlier studies found no link between treatment response and T_reg numbers. Data from autoimmune animal models suggest a different explanation: resistance of pathogenic CD4+ effector T cells (T_effs) to T_reg suppression may be what causes tolerance to fail in autoimmunity. This same T_eff resistance has also been reported in human autoimmune diseases like type 1 diabetes mellitus (T1D), rheumatoid arthritis (RA), and psoriasis. Several factors can trigger T_eff resistance, including tumor necrosis factor–α (TNF-α), interleukin-4 (IL-4), IL-12, IL-6, IL-7, IL-15, IL-21, and the maturation state of CD4 T-cells.

IL-6 and T-Effector Cell Resistance

In a study published in Nature, Schneider’s group showed that individuals with aggressive RRMS display T_eff resistance. They also identified the role of interleukin-6 (IL-6) in driving that resistance to T_reg suppression.

Earlier research had already linked IL-6 to MS pathology. IL-6 inhibits apoptosis in T-cells, is required for T-helper 17 (T_H17) cell differentiation, and can make T_effs resistant to suppression after local exposure. During an inflammatory immune response, IL-6 levels rise quickly and bind to the IL-6 receptor α (IL-6Rα) on the surface of CD4 T-cells. This recruits Glycoprotein 130 (gp130) to the IL-6-IL-6R complex, activating and phosphorylating signal transducer and activator of transcription 3 (STAT3). IL-6 can also bind soluble IL-6Rα (sIL-6Rα) in the serum, triggering STAT3 phosphorylation through membrane-bound gp130 instead. Genetic variants in the STAT3 locus are already linked to MS susceptibility. RRMS patients also show a significant rise in phosphorylated STAT3 (pSTAT3) and IL-6Rα expression on CD4+ T cells.

What the Study Found

Schneider’s team investigated T_eff resistance in RRMS by comparing T_effs from RRMS patients and healthy individuals using T_reg suppression assays. T_eff resistance appeared only in patients with active disease (two or more clinical exacerbations, or one or more gadolinium-enhancing lesions on MRI within 2 years of sampling) — not in patients with inactive or mild disease.

When they ran suppression assays with a STAT3 inhibitor (blocking STAT3 phosphorylation), suppression improved. This points to a direct link between T_eff resistance and increased pSTAT3 in response to IL-6. The data suggest that higher IL-6Rα expression on CD4+ T-cells, combined with IL-6-driven STAT3 phosphorylation, are major drivers of the impaired suppression seen in RRMS patients. The researchers hypothesize that in active RRMS, elevated IL-6 production from microglia, astrocytes, endothelial cells, neurons, oligodendrocytes, or infiltrating T-cells in the CNS drives both the pSTAT3 increase and the resistance to T_reg regulation.

Implications for MS Research and Treatment

These findings suggest IL-6Rα expression and IL-6-mediated pSTAT3 could serve as new markers for tracking disease activity and treatment response — including response to immunomodulatory therapies like tocilizumab (an IL-6Rα antagonist) in RRMS. The study also used some unconventional technical approaches: testing IL-6’s impact on suppression in an antigen-presenting cell (APC)-free system, and using a bead-based stimulation assay plus in vitro-generated T_regs to keep activation and T_reg source consistent. These techniques were key to the study’s conclusions and should prove useful for future MS research.

Sanguine supplies research-grade human CD4+ T cells for studies like this.

Further Reading:

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

In vitro Treg Suppression Assays.