The IL23R A/Gln381 allele promotes IL-23 unresponsiveness in human memory T-helper 17 cells and impairs Th17 responses in psoriasis patients

J Invest Dermatol. 2013 Oct;133(10):2381-2389. doi: 10.1038/jid.2013.170. Epub 2013 Apr 5.


We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Female
  • Heterozygote
  • Homozygote
  • Humans
  • Immunologic Memory / genetics*
  • Immunologic Memory / immunology
  • Interleukin-23 / immunology*
  • Interleukin-23 / metabolism
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Polymorphism, Single Nucleotide / immunology
  • Psoriasis / genetics*
  • Psoriasis / immunology*
  • Receptors, Interleukin / genetics*
  • Receptors, Interleukin / immunology
  • Receptors, Interleukin / metabolism
  • Th17 Cells / immunology*
  • Young Adult


  • IL23R protein, human
  • Interleukin-23
  • Receptors, Interleukin