Gut Inflammation in Axial Spondyloarthritis Patients is Characterized by a Marked Type 17 Skewed Mucosal Innate‐like T Cell Signature

Abstract

ObjectivePatients with spondyloarthritis (SpA) often present with microscopic signs of gut inflammation, a risk factor for progressive disease. We investigated whether mucosal innate‐like T cells are involved in dysregulated interleukin‐23 (IL‐23)/IL‐17 responses in the gut‐joint axis in SpA.MethodsIleal and colonic intraepithelial lymphocytes (IELs), lamina propria lymphocytes (LPLs), and paired peripheral blood mononuclear cells (PBMCs) were isolated from treatment‐naive patients with nonradiographic axial SpA with (n = 11) and without (n = 14) microscopic gut inflammation and healthy controls (n = 15) undergoing ileocolonoscopy. The presence of gut inflammation was assessed histopathologically. Immunophenotyping of innate‐like T cells and conventional T cells was performed using intracellular flow cytometry. Unsupervised clustering analysis was done by FlowSOM technology. Serum IL‐17A levels were measured via Luminex.ResultsMicroscopic gut inflammation in nonradiographic axial SpA was characterized by increased ileal intraepithelial γδ‐hi T cells, a γδ‐T cell subset with elevated γδ‐T cell receptor expression. γδ‐hi T cells were also increased in PBMCs of patients with nonradiographic axial SpA versus healthy controls and were strongly associated with Ankylosing Spondylitis Disease Activity Score. The abundance of mucosal‐associated invariant T cells and invariant natural killer T cells was unaltered. Innate‐like T cells in the inflamed gut showed increased RORγt, IL‐17A, and IL‐22 levels with loss of T‐bet, a signature that was less pronounced in conventional T cells. Presence of gut inflammation was associated with higher serum IL‐17A levels. In patients treated with tumor necrosis factor blockade, the proportion of γδ‐hi cells and RORγt expression in blood was completely restored.ConclusionIntestinal innate‐like T cells display marked type 17 skewing in the inflamed gut mucosa of patients with nonradiographic axial SpA. γδ‐hi T cells are linked to intestinal inflammation and disease activity in SpA.