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Prevention of autoimmune gastritis in mice requires extra-thymic T-cell deletion and suppression by regulatory T cells.
Gastroenterology 2007; 133(2):547-58G

Abstract

BACKGROUND AND AIMS

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.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17603058

Citation

Read, Simon, et al. "Prevention of Autoimmune Gastritis in Mice Requires Extra-thymic T-cell Deletion and Suppression By Regulatory T Cells." Gastroenterology, vol. 133, no. 2, 2007, pp. 547-58.
Read S, Hogan TV, Zwar TD, et al. Prevention of autoimmune gastritis in mice requires extra-thymic T-cell deletion and suppression by regulatory T cells. Gastroenterology. 2007;133(2):547-58.
Read, S., Hogan, T. V., Zwar, T. D., Gleeson, P. A., & Van Driel, I. R. (2007). Prevention of autoimmune gastritis in mice requires extra-thymic T-cell deletion and suppression by regulatory T cells. Gastroenterology, 133(2), pp. 547-58.
Read S, et al. Prevention of Autoimmune Gastritis in Mice Requires Extra-thymic T-cell Deletion and Suppression By Regulatory T Cells. Gastroenterology. 2007;133(2):547-58. PubMed PMID: 17603058.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prevention of autoimmune gastritis in mice requires extra-thymic T-cell deletion and suppression by regulatory T cells. AU - Read,Simon, AU - Hogan,Thea V, AU - Zwar,Tricia D, AU - Gleeson,Paul A, AU - Van Driel,Ian R, Y1 - 2007/06/02/ PY - 2006/05/24/received PY - 2007/05/10/accepted PY - 2007/7/3/pubmed PY - 2007/9/7/medline PY - 2007/7/3/entrez SP - 547 EP - 58 JF - Gastroenterology JO - Gastroenterology VL - 133 IS - 2 N2 - BACKGROUND AND AIMS: 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. SN - 0016-5085 UR - https://www.unboundmedicine.com/medline/citation/17603058/Prevention_of_autoimmune_gastritis_in_mice_requires_extra_thymic_T_cell_deletion_and_suppression_by_regulatory_T_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(07)01101-8 DB - PRIME DP - Unbound Medicine ER -