TNF-α orchestrates CD4+ T cell-dependent inflammation via TNFR2 signaling

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Abstract CD4+ T helper subsets, in particular Th1 and Th17, produce cytokines that play critical roles in inflammatory diseases. TNF-α, produced largely by innate immune cells, is also potently pro-inflammatory. Here we asked if TNF-α contributes to effector CD4+ Th generation, and found that in the presence of TGF-β TNF-α signals via its non-death receptor TNFR2 to generate Th17 cells expressing inflammatory mediators such as GM-CSF, CXCL3, and IFN-γ. Single cell RNA-Seq of CNS-infiltrating CD4+ T cells in EAE identified an IL-17-positive cluster with an inflammatory gene signature that required TNFR2 expression. Notably, TNFR2-deficient CD4+ T cells produced fewer inflammatory mediators and were relatively nonpathogenic in EAE and colitis. Thus, TNF-α is not just an effector but also an initiator of Th differentiation, raising the possibility that in diseases in which both TNF-α and IL-17 contribute, targeting TNF-α may diminish the generation of pathogenic Th17 cells.