TNF plays a crucial role in inflammation by signaling via T cell TNFR2

Abstract

Abstract TNF, produced largely by T and innate immune cells, is potently pro-inflammatory, as are cytokines such as IFN-γ and IL-17 produced by Th1 and Th17 cells, respectively. Analysis of single-cell RNA-Seq datasets from multiple sclerosis (MS) patients identified CSF-infiltrating CD4+ T cells that had inflammatory gene signatures including high levels of TNF. This prompted us to ask if TNF is upstream of Th skewing toward inflammatory phenotypes. We found that exposure of naive human or mouse CD4+ T cells to TNF and TGF-β generated Th17 cells that express low levels of IL-17 (RORγt+IL-17lo) and high levels of inflammatory markers, independently of IL-6 and STAT3. This was mediated by the non-death TNF receptor TNFR2, which was also found to contribute to the generation of inflammatory Th1 cells. Single-cell RNA-seq of CNS-infiltrating CD4+ T cells in mouse experimental autoimmune encephalomyelitis (EAE) found an inflammatory gene expression profile similar to MS. Notably, TNFR2-deficient CD4+ T cells produced fewer inflammatory mediators and were less pathogenic in EAE and colitis. IL-1β, a Th17-skewing cytokine, induced TNF and pro-inflammatory GM-CSF in both human and mouse T cells, which was prevented by disruption of TNFR2 signaling, demonstrating IL-1β can function indirectly via the production of TNF. Thus, TNF is not just an effector cytokine but also an initiator of inflammatory Th differentiation, raising the possibility that targeting TNFR2 may diminish the generation of pathogenic Th cells in diseases in which TNF, IFN-γ, and IL-17 contribute.