Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation

T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes, and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate, which induced cell stress and changes in biosynthesis of cholesterol and lipids, as revealed by single-cell RNA-sequencing analysis. Finally, exposure to glutamate decreased myelination, whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities in MS.

Multiple sclerosis (MS) is a disabling inflammatory disease of the central nervous system (CNS) characterized by demyelination as a key pathological hallmark (1). Loss of metabolic support and axonal myelination provided by oligodendrocytes not only impairs neurotransmission but also compromises neuronal homeostasis, leading to neuroaxonal vulnerability (2, 3). Chronic demyelination is therefore considered to play a major role in the progression of neurological disability in MS (4–6). The pharmacological protection of oligodendrocytes has been discussed as a new therapeutic strategy for MS (7) and is especially appealing in light of recent results showing that oligodendrocyte damage is partially reversible (8). However, the mechanisms underlying immune-mediated oligodendrocyte injury in neuroinflammation are still only partially understood.Proinflammatory CD4⁺ T cells are considered to play a major role in neuroinflammatory processes in MS and in its animal model, experimental autoimmune encephalomyelitis (EAE) (9–11). In particular, interleukin (IL)-23–polarized T helper (Th)17 cells coexpressing T-bet and ROR-γ are considered pathogenic in both EAE (12, 13) and in MS (13–15). Interestingly, in MS subjects, reduced Th17 responses after hematopoietic stem cell transplantation (16) or the exclusion of the double-positive Th17/1 cells from the CNS compartment after treatment with natalizumab (17) is associated with a dramatic decrease in the accumulation or expansion of demyelinating lesions, while interfering with IL-17A-cytokine signaling had moderate effects on disease severity (18). The capacity of IL-23–skewed Th17 cells to destabilize the blood–brain barrier (BBB) and recruit antigen-presenting cells to the CNS compartment in neuroinflammation is well established (13, 19, 20), but it is not clear whether Th17 cells cause tissue injury themselves. Previous studies have demonstrated that activated CD4⁺ T cells can exert cytotoxicity toward human and rodent oligodendrocytes (21–23) in vitro and impair remyelination in a toxic mouse model (24). Of note, older in vitro reports, from prior to the discovery of Th17 cells, using human oligodendrocytic cell lines rather excluded a soluble cytokine mediator of adult oligodendrocyte lysis (21, 25). Therefore, our goal was to unravel the direct influence of Th17 cells on the myelin compartment in neuroinflammation.