Endogenous H/K ATPase beta-subunit promotes T cell tolerance to the immunodominant gastritogenic determinant.
A CD4(+) T cell response to the gastric H/K ATPase beta-subunit (H/Kbeta) is required for the onset of experimental autoimmune gastritis in BALB/c mice. The extent to which endogenous H/Kbeta contributes toward the tolerance of the H/Kbeta-specific T cell repertoire in normal individuals is not known. By comparison of T cell responses in H/Kbeta-deficient (o/o) and H/Kbeta-expressing BALB/c mice, in this work we show that the endogenous H/Kbeta autoantigen plays a major role in the tolerance of pathogenic H/Kbeta-specific T cells. First, T cell-dependent Ab responses to the H/Kbeta Ag were enhanced in H/K ATPase-immunized H/Kbeta-deficient mice compared with wild-type mice. Second, peptide immunization experiments indicated that immune responses to the major gastritogenic epitope of the H/K ATPase, namely H/Kbeta(253-277), were significantly more vigorous in H/Kbeta-deficient mice compared with wild-type mice. Third, unfractionated splenocytes from H/Kbeta-deficient mice, but not H/Kbeta-expressing mice, induced autoimmune gastritis after adoptive transfer to BALB/c nude mice. The enhanced responses to H/Kbeta in H/Kbeta-deficient mice were shown to be intrinsic to CD4(+)CD25(-) T cells rather than a change in status of CD4(+)CD25(+) regulatory T cells. We conclude from these studies that the H/Kbeta-specific T cells in wild-type mice represent the residue of a T cell repertoire, directed toward a single determinant, that has been subjected to partial tolerance induction.
Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria, Australia.
Karen L
KL
Laurie
Ian R
IR
Van Driel
Tricia D
TD
Zwar
Simon P
SP
Barrett
Paul A
PA
Gleeson
D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D001327:Autoimmune Diseases / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005756:Gastritis / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D017506:H(+)-K(+)-Exchanging ATPase / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007108:Immune Tolerance / Q000235:genetics; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D010446:Peptide Fragments / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology*
D001323:Autoantibodies; D001324:Autoantigens; D015704:CD4 Antigens; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D015375:Receptors, Interleukin-2; D017506:H(+)-K(+)-Exchanging ATPase