IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2+Vγ6+γδ T cells

Abstract

Interleukin-17 (IL-17)-producing γδ T (γδ17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4+ and γδ17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4+ T cells direct γδ T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vγ6+ subset of CCR2+ γδ T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on γδ T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vγ6+ cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner.

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…The ‘ready‐to‐go’ phenotype of γδ 17 cells is especially efficient for early‐stage pathogen clearance. A combination of IL‐1 β and IL‐23, but not IL‐1 β or IL‐23 alone, is required to induce IL‐17 by γδ 17 cells 20. Further study revealed that IL‐23 is required for the induction of IL‐1R, and IL‐1 β is essential for the induction of IL‐17 20.…”

“…However, because IL‐1 β alone does not induce IL‐17 production in Il1rn −/− mouse‐derived splenic γδ T cells20 and in normal peritoneum‐ and lung‐derived γδ T cells, in which high levels of IL‐1R are expressed,48 IL‐23 may play other roles than up‐regulating IL‐1R in the induction of IL‐17 expression in γδ T cells. In this context, ROR γ t expression is up‐regulated by IL‐1 β and IL‐23 in a synergistic manner 20. The inflammatory cytokine IL‐18,53 complement C5a,54 the ligand of Toll‐like receptors 1 and 2, and dectin‐155 also induce IL‐17 in collaboration with IL‐23.…”

“…A combination of IL‐1 β and IL‐23, but not IL‐1 β or IL‐23 alone, is required to induce IL‐17 by γδ 17 cells 20. Further study revealed that IL‐23 is required for the induction of IL‐1R, and IL‐1 β is essential for the induction of IL‐17 20. However, because IL‐1 β alone does not induce IL‐17 production in Il1rn −/− mouse‐derived splenic γδ T cells20 and in normal peritoneum‐ and lung‐derived γδ T cells, in which high levels of IL‐1R are expressed,48 IL‐23 may play other roles than up‐regulating IL‐1R in the induction of IL‐17 expression in γδ T cells.…”

“…Il1rn −/− mice develop arthritis spontaneously in an IL‐17‐dependent manner 7. In these mice, however, only γδ 17 cells are the IL‐17 producer in the joints, although both γδ 17 cells and Th17 cells are detected in the draining lymph nodes 20. IL‐17‐GFP reporter mice reveal that the V γ 6 + /V δ 1 + cells predominantly produce IL‐17 in affected joints.…”

“…On the other hand, a gene array analysis shows that the expression of chemokine receptors such as CCR6, CCR2 and CXCR6 is already up‐regulated in γδ 17 cells during thymic development 34. Recent studies have indicated that the CCL20–CCR6 axis is mainly required for γδ 17 cell recruitment into homeostatic sites such as dermis,70 whereas the CCL2–CCR2 axis recruits γδ 17 cells into inflammatory sites, including psoriatic skin,71 arthritic joints,20 central nervous system in EAE, infected mucosal tissues and tumours 70. Interestingly, γδ 17 cells constitutively express both CCR2 and CCR6, but down‐regulate CCR6 expression after inflammation 70.…”