Immunodominant, Protective Response to the Parasite Toxoplasma Gondii Requires Antigen Processing in the Endoplasmic Reticulum

Nat Immunol. 2008 Aug;9(8):937-44. doi: 10.1038/ni.1629. Epub 2008 Jun 29.

Abstract

The parasite Toxoplasma gondii replicates in a specialized intracellular vacuole and causes disease in many species. Protection from toxoplasmosis is mediated by CD8(+) T cells, but the T. gondii antigens and host genes required for eliciting protective immunity are poorly defined. Here we identified GRA6, a polymorphic protein secreted in the parasitophorous vacuole, as the source of the immunodominant and protective decapeptide HF10 presented by the H-2L(d) major histocompatibility complex class I molecule. Presentation of the HF10-H-2L(d) ligand required proteolysis by ERAAP, the endoplasmic reticulum aminopeptidase associated with antigen processing. Consequently, expansion of protective CD8(+) T cell populations was impaired in T. gondii-infected ERAAP-deficient mice, which were more susceptible to toxoplasmosis. Thus, endoplasmic reticulum proteolysis is critical for eliciting protective immunity to a vacuolar parasite.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • Antigens, Protozoan / metabolism*
  • Endoplasmic Reticulum / immunology*
  • Histocompatibility Antigens Class I / immunology*
  • Leucyl Aminopeptidase / deficiency*
  • Leucyl Aminopeptidase / immunology
  • Leucyl Aminopeptidase / metabolism
  • Mice
  • Protozoan Proteins / metabolism*
  • Toxoplasma / immunology*
  • Toxoplasma / physiology
  • Toxoplasmosis / immunology*
  • Vacuoles / immunology

Substances

  • Antigens, Protozoan
  • GRA6 protein, Toxoplasma gondii
  • Histocompatibility Antigens Class I
  • Protozoan Proteins
  • Leucyl Aminopeptidase
  • puromycin-insensitive leucyl-specific aminopeptidase