A point mutation in the IL-12R beta 2 gene underlies the IL-12 unresponsiveness of Lps-defective C57BL/10ScCr mice

J Immunol. 2001 Aug 15;167(4):2106-11. doi: 10.4049/jimmunol.167.4.2106.

Abstract

Lps-defective C57BL/10ScCr (Cr) mice are homozygous for a deletion encompassing Toll-like receptor 4 that makes them refractory to the biological activity of LPS. In addition, these mice exhibit an inherited IL-12 unresponsiveness resulting in impaired IFN-gamma responses to different microorganisms. By positional cloning methods, we show here that this second defect of Cr mice is due to a mutation in a single gene located on mouse chromosome 6, in close proximity to the Igkappa locus. The gene is IL-12Rbeta2. Cr mice carry a point mutation creating a stop codon that is predicted to cause premature termination of the translated IL-12Rbeta2 after a lysine residue at position 777. The truncated beta2 chain can still form a heterodimeric IL-12R that allows phosphorylation of Janus kinase 2, but, unlike the wild-type IL-12R, can no longer mediate phosphorylation of STAT4. Because the phosphorylation of STAT4 is a prerequisite for the IL-12-mediated induction of IFN-gamma, its absence in Cr mice is responsible for their defective IFN-gamma response to microorganisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chromosome Mapping
  • Drosophila Proteins*
  • Gene Deletion*
  • Genetic Markers / immunology
  • Immune Tolerance / genetics*
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL / genetics*
  • Mice, Inbred C57BL / immunology*
  • Point Mutation*
  • Receptors, Cell Surface / genetics
  • Receptors, Interleukin / genetics*
  • Receptors, Interleukin / isolation & purification
  • Receptors, Interleukin / physiology
  • Receptors, Interleukin-12
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Toll-Like Receptors

Substances

  • Drosophila Proteins
  • Genetic Markers
  • Il12rb2 protein, mouse
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • Toll-Like Receptors
  • Interleukin-12
  • Interferon-gamma