Tolerance and autoimmunity to a gastritogenic peptide in TCR transgenic mice.
The catalytic alpha and glycoprotein beta subunits of the gastric H/K ATPase are major molecular targets in human and mouse autoimmune gastritis. We have previously shown that the H/K ATPase beta subunit is required for the initiation of mouse gastritis and identified a gastritogenic H/K ATPase beta subunit peptide (H/Kbeta253-277). Here we report the generation of MHC class II-restricted TCR transgenic mice using V(alpha)9 and V(beta)8.3 TCR chains with specificity for the gastritogenic H/Kbeta253-277 peptide. We found an 8-fold reduction in CD4(+) T cells in the thymus of the transgenic mice. Despite the reduction in intrathymic CD4(+) T cells, V(beta)8. 3-expressing T cells comprised the majority (>90%) of peripheral spleen and lymph node T cells. These peripheral T cells retained their capacity to proliferate in vitro to the H/Kbeta253-277 peptide. Using the responsive T cells, we have restricted the gastritogenic T cell epitope to H/Kbeta261-274. Despite the capacity of the peripheral T cells to proliferate in vitro to the peptide, the majority ( approximately 80%, 13 of 16) of transgenic mice remained free of gastritis while a minority (20%, three of 16) spontaneously developed an invasive and destructive gastritis. Our results confirm that H/Kbeta261-274 is a gastritogenic peptide. The data also suggest that CD4 T cell tolerance to the gastritogenic peptide in the transgenic mice is maintained by a combination of intrathymic and peripheral tolerance mechanisms.
Alderuccio
F
F
Department of Pathology and Immunology, Monash University Medical School, Commercial Road, Prahran, Victoria 3181, Australia.
Cataldo
V
V
van Driel
I R
IR
Gleeson
P A
PA
Toh
B H
BH
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005753:Gastric Mucosa / Q000276:immunology / Q000473:pathology; D005756:Gastritis / Q000276:immunology*; D017506:H(+)-K(+)-Exchanging ATPase / Q000737:chemistry / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D007437:Intrinsic Factor / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010295:Parietal Cells, Gastric / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013552:Swine; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology
D001323:Autoantibodies; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007437:Intrinsic Factor; D017506:H(+)-K(+)-Exchanging ATPase