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

Proceedings of the National Academy of Sciences of the United States of America

3 years ago

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

Muhammad S. Alam, Shizuka Otsuka, Nathan Wong, Aamna Abbasi, Matthias M. Gaida, Yu Fan, Daoud Meerzaman, Jonathan D. Ashwell

TNF, produced largely by T and innate immune cells, is potently proinflammatory, as are cytokines such as IFN-γ and IL-17 produced by Th1 and Th17 cells, respectively. Here, we asked if TNF is upstream of Th skewing toward inflammatory phenotypes. Exposure of mouse CD4⁺ T cells to TNF and TGF-β generated Th17 cells that express low levels of IL-17 (ROR-γt⁺IL-17^lo) and high levels of inflammatory markers independently of IL-6 and STAT3. This was mediated by the nondeath TNF receptor TNFR2, which also contributed to the generation of inflammatory Th1 cells. Single-cell RNA sequencing of central nervous system–infiltrating CD4⁺ T cells in mouse experimental autoimmune encephalomyelitis (EAE) found an inflammatory gene expression profile similar to cerebrospinal fluid–infiltrating CD4⁺ T cells from patients with multiple sclerosis. 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 proinflammatory granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, which was inhibited by disruption of TNFR2 signaling, demonstrating IL-1β can function indirectly via the production of TNF. Thus, TNF is not just an effector but also an initiator of inflammatory Th differentiation.

Publisher URL: https://www.pnas.org/content/118/50/e2109972118.short

DOI: 10.1073/pnas.2109972118