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

作者：Ng Dennis; Maitre Blandine; Cummings Derek; Lin Albert; Ward Lesley A; Rahbar Ramtin; Mossman Karen L; Ohashi Pamela S; Gommerman Jennifer L^*

来源：The Journal of Immunology, 2015, 195(10): 4650-4659.

DOI：10.4049/jimmunol.1501053

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-beta receptor (LT beta R) 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 LTbR 2/2 DC could be rescued by exogenous addition of IFN-I. Collectively, our data demonstrate that the LT beta R/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/LT beta R axis will provide valuable therapeutic insights for treatment of CD8(+) T cell-mediated autoimmune diseases.

• 出版日期2015-11-15