IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells

Nat Med. 2012 Jul 1;18(7):1069-76. doi: 10.1038/nm.2817.


The spondyloarthropathies are a group of rheumatic diseases that are associated with inflammation at anatomically distal sites, particularly the tendon-bone attachments (entheses) and the aortic root. Serum concentrations of interleukin-23 (IL-23) are elevated and polymorphisms in the IL-23 receptor are associated with ankyosing spondylitis, however, it remains unclear whether IL-23 acts locally at the enthesis or distally on circulating cell populations. We show here that IL-23 is essential in enthesitis and acts on previously unidentified IL-23 receptor (IL-23R)(+), RAR-related orphan receptor γt (ROR-γt)(+)CD3(+)CD4(-)CD8(-), stem cell antigen 1 (Sca1)(+) entheseal resident T cells. These cells allow entheses to respond to IL-23 in vitro-in the absence of further cellular recruitment--and to elaborate inflammatory mediators including IL-6, IL-17, IL-22 and chemokine (C-X-C motif) ligand 1 (CXCL1). Notably, the in vivo expression of IL-23 is sufficient to phenocopy the human disease, with the specific and characteristic development of enthesitis and entheseal new bone formation in the initial complete absence of synovitis. As in the human condition, inflammation also develops in vivo at the aortic root and valve, which are structurally similar to entheses. The presence of these entheseal resident cells and their production of IL-22, which activates signal transducer and activator of transcription 3 (STAT3)-dependent osteoblast-mediated bone remodeling, explains why dysregulation of IL-23 results in inflammation at this precise anatomical site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Aorta / pathology
  • Arthritis, Experimental / complications
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / pathology
  • Bone Remodeling
  • CD3 Complex / metabolism
  • CD4 Antigens / metabolism
  • CD8 Antigens / metabolism
  • Disease Models, Animal
  • Extremities / pathology
  • Flow Cytometry
  • Humans
  • Immunization, Passive
  • Inflammation / complications
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-17
  • Interleukin-22
  • Interleukin-23 / immunology*
  • Interleukins
  • Mice
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Osteogenesis / immunology
  • Periosteum / growth & development
  • Receptors, Interleukin / metabolism
  • Spondylarthropathies / complications
  • Spondylarthropathies / immunology*
  • Spondylarthropathies / pathology
  • T-Lymphocytes / immunology*
  • Tendons / immunology*
  • Tendons / pathology
  • Th17 Cells


  • Antigens, CD
  • CD3 Complex
  • CD4 Antigens
  • CD8 Antigens
  • Interleukin-17
  • Interleukin-23
  • Interleukins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Interleukin
  • interleukin-23 receptor, mouse