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

Significance Inflammatory diseases are mediated by products such as TNF and IL-17 produced by T helper (Th) cell subsets. Here, we identify a direct role for TNF in the production of pathogenic T cells, particularly cells that produce IL-17 (Th17) and interferon-γ (Th1). We found that TNF shapes the inflammatory response by signaling via its relatively unstudied “minor” receptor, TNFR2, skewing T cells to become inflammatory Th17 cells and enhancing inflammatory cytokine production by Th1 cells. Preventing TNFR2 signaling resulted in reduced disease in mouse models of multiple sclerosis and colitis. This work integrates the importance of TNF with Th17/Th1 cell pathogenicity and may explain the paradox that IL-17–dependent diseases, such as psoriasis and ankylosing spondylitis, respond to anti-TNF monotherapy.