title: Antigen stability controls antigen presentation.
abstract: We investigated whether protein stability controls antigen presentation using a four disulfide-containing snake toxin and three derivatives carrying one or two mutations (L1A, L1A/H4Y, and H4Y). These mutations were anticipated to increase (H4Y) or decrease (L1A) the antigen non-covalent stabilizing interactions, H4Y being naturally and frequently observed in neurotoxins. The chemically synthesized derivatives shared similar three-dimensional structure, biological activity, and T epitope pattern. However, they displayed differential thermal unfolding capacities, ranging from 65 to 98 degrees C. Using these differentially stable derivatives, we demonstrated that antigen stability controls antigen proteolysis, antigen processing in antigen-presenting cells, T cell stimulation, and kinetics of expression of T cell determinants. Therefore, non-covalent interactions that control the unfolding capacity of an antigen are key parameters in the efficacy of antigen presentation. By affecting the stabilizing interaction network of proteins, some natural mutations may modulate the subsequent T-cell stimulation and might help microorganisms to escape the immune response.
authors.affiliation: Département d'Ingénierie et d'Etudes des Protéines, Commissariat à l'Energie Atomique, C.E. Saclay, 91191 Gif-sur-Yvette, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Thai
authors.forename: Gervaise
authors.initials: G
authors.lastname: Moine
authors.forename: Michel
authors.initials: M
authors.lastname: Desmadril
authors.forename: Denis
authors.initials: D
authors.lastname: Servent
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Tarride
authors.forename: André
authors.initials: A
authors.lastname: Ménez
authors.forename: Michel
authors.initials: M
authors.lastname: Léonetti
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D002942:Circular Dichroism; D003039:Cobra Neurotoxin Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013601:T-Lymphocytes / Q000276:immunology; D013696:Temperature; D013816:Thermodynamics
chemical_list: D003039:Cobra Neurotoxin Proteins; D000939:Epitopes; C025154:alpha-cobratoxin