RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients

Nat Commun. 2019 Jan 2;10(1):9. doi: 10.1038/s41467-018-07911-6.


Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). RORγt, the key Thelper17 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells, but their contribution to SpA is still unclear. Here we describe the presence of particular RORγt+T-betloPLZF- iNKT and γδ-hi T cell subsets in healthy peripheral blood. RORγt+ iNKT and γδ-hi T cells show IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and γδ-T cells showed unique and Th17-skewed phenotype and gene expression profiles. Strikingly, RORγt inhibition blocked γδ17 and iNKT17 cell function while selectively sparing IL-22+ subsets. Overall, our findings highlight a unique diversity of human RORγt+ T cells and underscore the potential of RORγt antagonism to modulate aberrant type 17 responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Humans
  • Interleukin-17 / metabolism
  • Natural Killer T-Cells / metabolism*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Receptors, Interleukin / metabolism
  • Spondylarthritis / immunology*
  • T-Lymphocyte Subsets / metabolism*


  • IL23R protein, human
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Interleukin