A T17-intrinsic IL-1β-STAT5 axis drives steroid resistance in autoimmune neuroinflammation.

Steroid resistance poses a major challenge for the management of autoimmune neuroinflammation. T helper 17 (T17) cells are widely implicated in the pathology of steroid resistance; however, the underlying mechanisms are unknown. In this study, we identified that interleukin-1 receptor (IL-1R) blockade rendered experimental autoimmune encephalomyelitis (EAE) mice sensitive to dexamethasone (Dex) treatment. Interleukin-1β (IL-1β) induced a signal transducer and activator of transcription 5 (STAT5)-mediated steroid-resistant transcriptional program in T17 cells, which promoted inflammatory cytokine production and suppressed Dex-induced anti-inflammatory genes. T17-specific deletion of STAT5 ablated the IL-1β-induced steroid-resistant transcriptional program and rendered EAE mice sensitive to Dex treatment. IL-1β synergized with Dex to promote the STAT5-dependent expression of CD69 and the development of central nervous system (CNS)-resident CD69 T17 cells. Combined IL-1R blockade and Dex treatment ablated CNS-resident T17 cells, reduced EAE severity, and prevented relapse. CD69 tissue-resident T17 cells were also detected in brain lesions of patients with multiple sclerosis. These findings (i) demonstrate that IL-1β-STAT5 signaling in T17 cells mediates steroid resistance and (ii) identify a therapeutic strategy for reversing steroid resistance in T17-mediated CNS autoimmunity.