Prevention of autoimmune gastritis in mice requires extra-thymic T-cell deletion and suppression by regulatory T cells.
OBJECTIVE
Autoimmune gastritis is one of the most common autoimmune diseases and is caused by a CD4(+) T-cell response to the gastric H(+)/K(+) ATPase encoded by Atp4a and Atp4b (H(+)/K(+) ATPase). Here, we have elucidated events that result in immunological tolerance to the H(+)/K(+) ATPase and thus the prevention of autoimmune gastritis.


METHODS
T cells from H(+)/K(+) ATPase-deficient mice and H(+)/K(+) ATPase-specific T-cell receptor transgenic mice were purified and transferred to wild-type (WT) or H(+)/K(+) ATPase-deficient recipients to assess the impact of exposure to antigen on pathogenicity.


RESULTS
The CD4(+) T-cell population from H(+)/K(+) ATPase-deficient mice was highly effective at inducing gastritis when compared with T cells from WT mice and, as a population, was comparatively resistant to the suppressive activity of regulatory T cells. Exposing T cells from H(+)/K(+) ATPase-deficient mice to H(+)/K(+) ATPase in WT mice decreased their ability to induce gastritis and resulted in a population that could be more easily suppressed by T(reg) cells. Transfer of clonotypic antigen-inexperienced H(+)/K(+) ATPase-specific T cells into WT mice resulted in extra-thymic clonal deletion.


CONCLUSIONS
Prevention of autoimmune gastritis requires the extra-thymic purging of highly autoaggressive H(+)/K(+) ATPase-specific T cells to produce a T-cell repertoire that is more susceptible to the suppressive activity of regulatory T cells. Taken together with recent published data describing the role of T-cell receptor signalling in the maintenance of regulatory T-cell populations, we propose that exposure of T cells to antigen in the periphery is able to both delete autoaggressive specificities and maintain regulatory T-cell activity, establishing a balance between pathogenicity and regulation.
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Simon
S
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
Hogan
Thea V
TV
Zwar
Tricia D
TD
Gleeson
Paul A
PA
Van Driel
Ian R
IR
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005756:Gastritis / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D017506:H(+)-K(+)-Exchanging ATPase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D010049:Ovarian Diseases / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000637:transplantation
D001324:Autoantigens; D053645:Interleukin-2 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D017506:H(+)-K(+)-Exchanging ATPase