Prevention of autoimmune gastritis in mice requires extra-thymic T-cell deletion and suppression by regulatory T cells.
Gastroenterology
; 133(2): 547-58, 2007 Aug.
Article
en En
| MEDLINE
| ID: mdl-17603058
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autoantígenos
/
Enfermedades Autoinmunes
/
Linfocitos T CD4-Positivos
/
Depleción Linfocítica
/
Linfocitos T Reguladores
/
ATPasa Intercambiadora de Hidrógeno-Potásio
/
Gastritis
/
Tolerancia Inmunológica
Límite:
Animals
Idioma:
En
Revista:
Gastroenterology
Año:
2007
Tipo del documento:
Article
País de afiliación:
Australia
Pais de publicación:
Estados Unidos