Korn and colleagues report that Sirpα+ dendritic cells trans-present the cytokine IL-6 to T cells through a process that requires its receptor IL-6Rα bound to dendritic cells and that trans-presentation is needed to generate pathogenic cells of the TH17 subset of helper T cells in vivo. The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the TH17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic TH17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα+ DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic TH17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of TH17-cell-mediated autoimmune diseases.

Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.

See Petzold (doi: 10.1093/aww239 ) for a scientific commentary on this article . Assessment of inflammatory disease activity during multiple sclerosis is crucial for selecting appropriate disease-modifying therapies. Previous studies suggested that the retinal inner nuclear layer reflects inflammatory disease severity within the central nervous system. In our study, correlations of longitudinal retinal layer changes as measured by retinal optical coherence tomography with ongoing disease activity were evaluated in 108 multiple sclerosis patients without therapy, on first-line therapy, or on second-line therapy. Healthy subjects served as controls. Inner nuclear layer volume at baseline correlated positively with paraclinical disease activity during the subsequent 12 months. Longitudinal thinning of the inner nuclear layer and thickening of total macular volume were associated with reduced inflammatory disease activity. Reduction in inner nuclear layer volume after 1 year indicated efficient control of inflammatory disease activity including ‘no evidence of disease activity’. In conclusion, the retinal inner nuclear layer could serve as biomarker to monitor sustained control of autoimmune central nervous system inflammation by therapeutic interventions.

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS) and an important cause of sustained disability in young adults.¹ Early disease-modifying therapy of MS can improve long-term outcome and reduce the accrual of irreversible disability, which makes timely and accurate diagnosis of MS imperative.^2,3 The cause of MS is unknown,⁴ and in absence of a specific pathologic correlate, current diagnostic criteria rely on clinical presentation and typical MS lesions obtained in magnetic resonance imaging (MRI).⁵ Either way, dissemination of clinical or radiographic disease activity needs to be proven both in space and time.