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J Immunol. 2015 Nov 15;195(10):4650-9. doi: 10.4049/jimmunol.1501053. Epub 2015 Oct 12.

A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology.

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Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada; and.
Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada.
Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;


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-β receptor (LTβR) 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 LTβR(-/-) DC could be rescued by exogenous addition of IFN-I. Collectively, our data demonstrate that the LTβR/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/LTβR axis will provide valuable therapeutic insights for treatment of CD8(+) T cell-mediated autoimmune diseases.

[Indexed for MEDLINE]
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