RUNX2 is a cell-intrinsic brake on Th17 pathogenicity driven by neutrophil extracellular traps

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Abstract Th17 cells are crucial mediators of protective immunity against extracellular pathogens but also promote inflammatory responses in pathological settings such as MS. Distinct transcriptional programs can generate Th17 populations termed pathogenic or non-pathogenic. Understanding the transcriptional regulation of these T cell states is emerging and presents opportunities to modulate pathogenic T cell responses. In this study, we demonstrate that pro-inflammatory Th17 cells in MS and EAE express high levels of the transcription factor RUNX2. T cell specific deletion of RUNX2 lowers the threshold for induction of CNS autoimmunity in mice by increasing generation of pathogenic GM-CSF-expressing Th17 cells. RUNX2-dependent inhibition of pathogenic Th17 priming relied on the extent of neutrophil-driven pathogenic Th17 priming in vivo . EAE-induced immature neutrophils elicit more pathogenic Th17 cells in the absence of RUNX2 in T cells, an effect reliant on neutrophil-derived extracellular traps. These data uncover a role for RUNX2 in suppressing NET-driven Th17 pathogenicity and suggest that increasing RUNX2 activity in T cells may be a strategy to constrain pathological inflammatory responses where Th17 cells and inflammatory neutrophils interplay.

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