Cytokine competent gut-joint migratory T Cells contribute to inflammation in the joint

Abstract

Although studies have identified the presence of gut-associated cells in the enthesis of joints affected by spondylarthritis (SpA), a direct link through cellular transit between the gut and joint has yet to be formally demonstrated. Using KikGR transgenic mice to label in situ and track cellular trafficking from the distal colon to the joint under inflammatory conditions of both the gut and joint, we demonstrate bona-fide gut-joint trafficking of T cells from the colon epithelium, also called intraepithelial lymphocytes (IELs), to distal sites including joint enthesis, the pathogenic site of SpA. Similar to patients with SpA, colon IELs from the TNFΔARE/+ mouse model of inflammatory bowel disease and SpA display heightened TNF production upon stimulation. Using ex vivo stimulation of photo-labeled gut-joint trafficked T cells from the popliteal lymph nodes of KikGR and KikGR TNFΔARE/+ we saw that the CD4+ photo-labeled population was highly enriched for IL-17 competence in healthy as well as arthritic mice, however in the TNFΔARE/+ mice these cells were additionally enriched for TNF. Using transfer of magnetically isolated IELs from TNF+/+ and TNFΔARE/+ donors into Rag1-/- hosts, we confirmed that IELs can exacerbate inflammatory processes in the joint. Finally, we blocked IEL recruitment to the colon epithelium using broad spectrum antibiotics in TNFΔARE/+ mice. Antibiotic-treated mice had reduced gut-joint IEL migration, contained fewer Il-17A and TNF competent CD4+ T cells, and lessened joint pathology compared to untreated littermate controls. Together these results demonstrate that pro-inflammatory colon-derived IELs can exacerbate inflammatory responses in the joint through systemic trafficking, and that interference with this process through gut-targeted approaches has therapeutic potential in SpA.

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

“…Another limitation is that, although systemic IL-17 levels were higher in patients with SpA with gut inflammation, we did not prove a causal relationship with joint pathology. A recent study, however, demonstrated gut-joint trafficking of intraepithelial T cells in a tumor necrosis factor-driven SpA model (39), supporting the idea that mucosal IL-17 potentially contributes to arthritis. Future work is required to formally assess this, including in IL-23-driven models, which are also characterized by a dominant γδ-T cell-driven IL-17 response (40).…”

Intravital imaging of splenic classical monocytes modifying the hepatic CX3CR1+ cells motility to exacerbate liver fibrosis via spleen-liver axis

“…KikGR as a photoconvertible Green-to-Red fluorescent protein has been used to label and track cell migration in different disease models, such as spondylarthritis 68 , skin infection 69 , 70 , tumor 71 , etc. In this study, CX3CR1-KikGR transgenic mice were generated and used to specifically track the migration of splenic CX3CR1 + cells from the spleen to the fibrotic liver in vivo (Figure 6 A-L and S18C-G).…”

Sterile triggers drive joint inflammation in TNF‐ and IL‐1β‐dependent mouse arthritis models

“…Furthermore, both IBD and SpA are diseases characterized by changes in microbial community structure, composition, and function, termed ‘dysbiosis,’ which is suggested to prime mucosal immune cells, which traffic from the gut to the joints and cause inflammation (Gracey et al , 2020 ; Qaiyum et al , 2021 ). Photoactivatable transgenic Kaede and KikGR mice have provided evidence for trafficking of intestinal immune cells to extraintestinal sites including the joints, and gut‐joint trafficking of colonic intraepithelial lymphocytes was demonstrated in TNF ΔARE mice (Morton et al , 2014 ; Lefferts et al , 2022 ). Despite various experimental findings supporting a causal link between gut and joint inflammation, it remains unclear whether joint inflammation is critically dependent on microbial triggers or inflammatory cues from the gut.…”