Eomes controls the development of Th17‐derived (non‐classic) Th1 cells during chronic inflammation

It is well accepted that Th17 cells are a highly plastic cell subset that can be easily directed toward the Th1 phenotype in vitro and also in vivo during inflammation. However, there is an ongoing debate regarding the reverse plasticity (conversion from Th1 to Th17). We show here that ectopic ROR‐γt expression can restore or initiate IL‐17 expression by non‐classic or classic Th1 cells, respectively, while common pro‐Th17 cytokine cocktails are ineffective. This stability of the Th1 phenotype is at least partially due to the presence of a molecular machinery governed by the transcription factor Eomes, which promotes IFN‐γ secretion while inhibiting the expression of ROR‐γt and IL‐17. By using a mouse model of T cell‐dependent colitis we demonstrate that Eomes controls non‐classic Th1 cell development also in vivo and promotes their pathogenic potential. Eomes expression associates to a highly inflammatory phenotype also in patients with juvenile idiopathic arthritis. Indeed, it favors the acquisition of a cytotoxic signature, and promotes the development of IFN‐γ+GM‐CSF+ cells that have been described to be pathogenic in chronic inflammatory disorders. Chronic inflammation leads to conversion of Th17 cells towards a non‐classic Th1 phenotype. We show in vitro and in vivo in a mouse model of colitis and in juvenile idiopathic arthritis patients that this process is Eomes‐dependent. Eomes acts inhibiting RORC2 and IL17 expression, while contemporary promoting IFNG and CSF2.