A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology.
J Immunol
; 195(10): 4650-9, 2015 Nov 15.
Article
en En
| MEDLINE
| ID: mdl-26459352
ABSTRACT
Type I IFNs (IFN-I) are cytokines that can mediate both immune suppression and activation. Dendritic cells (DC) are significant producers of IFN-I, and depending on the context (nature of Ag, duration of exposure to Ag), DC-derived IFN-I can have varying effects on CD8(+) T cell responses. In this study, we report that in the context of a CD8(+) T cell response to a self-Ag, DC-intrinsic expression of IFN regulatory factor 3 is required to induce optimal proliferation and migration of autoreactive CD8(+) T cells, ultimately determining their ability to infiltrate a target tissue (pancreas), and the development of glucose intolerance in rat insulin promoter-glycoprotein (RIP-GP) mice. Moreover, we show that signals through the lymphotoxin-ß receptor (LTßR) in DC are also required for the proliferation of autoreactive CD8(+) T cells, the upregulation of VLA4/LFA1 on activated CD8(+) T cells, and their subsequent infiltration into the pancreas both in vitro and in vivo. Importantly, the defects in autoreactive CD8(+) T cell proliferation, accumulation of CD8(+) T cells in the pancreas, and consequent glucose intolerance observed in the context of priming by LTßR(-/-) DC could be rescued by exogenous addition of IFN-I. Collectively, our data demonstrate that the LTßR/IFN-I axis is essential for programming of CD8(+) T cells to mediate immunopathology in a self-tissue. A further understanding of the IFN-I/LTßR axis will provide valuable therapeutic insights for treatment of CD8(+) T cell-mediated autoimmune diseases.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Autoantígenos
/
Enfermedades Autoinmunes
/
Interferón Tipo I
/
Autoinmunidad
/
Linfocitos T CD8-positivos
/
Receptor beta de Linfotoxina
Límite:
Animals
Idioma:
En
Revista:
J Immunol
Año:
2015
Tipo del documento:
Article