Cross-priming of diabetogenic T cells dissociated from CTL-induced shedding of beta cell autoantigens.
J Immunol
; 171(12): 6900-9, 2003 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-14662897
Cross-presentation of self Ags by APCs is key to the initiation of organ-specific autoimmunity. As MHC class I molecules are essential for the initiation of diabetes in nonobese diabetic (NOD) mice, we sought to determine whether the initial insult that allows cross-presentation of beta cell autoantigens in diabetes is caused by cognate interactions between naive CD8(+) T cells and beta cells. Naive splenic CD8(+) T cells from transgenic NOD mice expressing a diabetogenic TCR killed peptide-pulsed targets in the absence of APCs. To ascertain the role of CD8(+) T cell-induced beta cell lysis in the initiation of diabetes, we expressed a rat insulin promoter (RIP)-driven adenovirus E19 transgene in NOD mice. RIP-E19 expression inhibited MHC class I transport exclusively in beta cells and rendered these cells resistant to lysis by CD8(+) (but not CD4(+)) T cells, both in vitro and in vivo. Surprisingly, RIP-E19 expression impaired the accumulation of CD8(+) T cells in islets and delayed the onset of islet inflammation, without affecting the timing or magnitude of T cell cross-priming in the pancreatic lymph nodes, which is the earliest known event in diabetogenesis. These results suggest that access of beta cell autoantigens to the cross-presentation pathway in diabetes is T cell independent, and reveal a previously unrecognized function of MHC class I molecules on target cells in autoimmunity: local retention of disease-initiating clonotypes.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autoantígenos
/
Comunicación Celular
/
Islotes Pancreáticos
/
Presentación de Antígeno
/
Linfocitos T CD8-positivos
/
Citotoxicidad Inmunológica
/
Diabetes Mellitus Tipo 1
Idioma:
En
Revista:
J Immunol
Año:
2003
Tipo del documento:
Article
País de afiliación:
Canadá
Pais de publicación:
Estados Unidos