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

Nat Commun. 2015 Jun 25;6:7464. doi: 10.1038/ncomms8464.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / immunology*
  • Arthritis / metabolism
  • Autoimmune Diseases / metabolism*
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Gene Expression Regulation / immunology
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin 1 Receptor Antagonist Protein / metabolism*
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Joints / metabolism
  • Joints / pathology
  • Lymphocyte Activation / physiology*
  • Mice
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Interleukin-1 Type I / genetics
  • Receptors, Interleukin-1 Type I / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / physiology*

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • IL1R1 protein, mouse
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-17
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Interleukin-1 Type I