Persistence of IL-2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

Eur J Immunol. 2011 Dec;41(12):3495-505. doi: 10.1002/eji.201141654. Epub 2011 Oct 27.

Abstract

Compared with other T-helper subsets, Th17 cell numbers are very low in human blood but become elevated in chronic inflammatory diseases. In this study, we investigated mechanisms that may explain the frequent involvement of Th17 cells in autoimmune diseases such as uveitis. We compared Th17 and Th1 subsets and found that Th17 cells expressed lower IL-2 levels during Ag-priming and this correlated with their decreased susceptibility to activation-induced cell death (AICD). However, complete depletion of IL-2 with IL-2 neutralizing antibodies rendered Th17 cells as susceptible to apoptosis as Th1 cells, suggesting that the low levels of IL-2 produced by Th17 cells conferred survival advantages to this subset. We describe here a Th17 subtype that constitutively produces very low levels of IL-2 (Th17-DP). The Th17-DP population increased dramatically in the blood and retina of mice during experimental autoimmune uveitis, indicating their potential involvement in the etiology of uveitis. We further show that the majority of the memory Th17 cells in human blood are Th17-DP and are targets of daclizumab, an IL-2R antibody used in treating recalcitrant uveitis. Thus, Th17 cells may persist in tissues and contribute to chronic inflammation by limiting IL-2 production to levels that cannot provoke IL-2-induced AICD yet are sufficient to promote Th17 homeostatic expansion.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antibodies, Neutralizing / immunology
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / metabolism
  • Cell Death / immunology
  • Daclizumab
  • Humans
  • Immunoglobulin G / therapeutic use
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Interleukin-2 / immunology
  • Receptors, Interleukin-2 / metabolism
  • Th1 Cells / immunology
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Uveitis / genetics
  • Uveitis / immunology*
  • Uveitis / metabolism

Substances

  • Antibodies
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Immunoglobulin G
  • Interleukin-2
  • Receptors, Interleukin-2
  • Daclizumab