title: Availability of autoantigenic epitopes controls phenotype, severity, and penetrance in TCR Tg autoimmune gastritis.
abstract: We examined TCR:MHC/peptide interactions and in vivo epitope availability to explore the Th1- or Th2-like phenotype of autoimmune disease in two TCR Tg mouse models of autoimmune gastritis (AIG). The TCR of strains A23 and A51 recognize distinct IA(d)-restricted peptides from the gastric parietal cell H/K-ATPase. Both peptides form extremely stable MHC/peptide (MHC/p) complexes. All A23 animals develop a Th1-like aggressive, inflammatory AIG early in life, while A51 mice develop indolent Th2-like AIG at 6-8 wk with incomplete penetrance. A51 T cells were more sensitive than A23 to low doses of soluble antigen and to MHC/p complexes. Staining with IA(d)/peptide tetramers was only detectable on previously activated T cells from A51. Thus, despite inducing a milder AIG, the A51 TCR displays a higher avidity for its cognate IA(d)/peptide. Nonetheless, in vivo proliferation of adoptively transferred A51 CFSE-labeled T cells in the gastric lymph node was relatively poor compared with A23 T cells. Also, DC from WT gastric lymph node, presenting processed antigen available in vivo, stimulated proliferation of A23 T cells better than A51. Thus, the autoimmune potential of these TCR in their respective Tg lines is strongly influenced by the availability of the peptide epitope, rather than by differential avidity for their respective MHC/p complexes.
authors.affiliation: Department of Biotechnology Engineering, Ort Braude College, Karmiel, Israel.
authors.forename: Ditza
authors.initials: D
authors.lastname: Levin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: DiPaolo
authors.forename: Carine
authors.initials: C
authors.lastname: Brinster
authors.forename: Maria Jamela R
authors.initials: MJ
authors.lastname: Revilleza
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Boyd
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
authors.forename: Kannan
authors.initials: K
authors.lastname: Natarajan
authors.forename: Michael G
authors.initials: MG
authors.lastname: Mage
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shevach
authors.forename: David H
authors.initials: DH
authors.lastname: Margulies
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D027682:Cation Transport Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005756:Gastritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; D027682:Cation Transport Proteins; D000939:Epitopes; D010455:Peptides; D011948:Receptors, Antigen, T-Cell