title: A Lymphotoxin/Type I IFN Axis Programs CD8+ T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology.
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-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.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Dennis
authors.initials: D
authors.lastname: Ng
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Blandine
authors.identifier: http://orcid.org/0000-0002-3264-7330
authors.initials: B
authors.lastname: Maître
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada; and.
authors.forename: Derek
authors.initials: D
authors.lastname: Cummings
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Albert
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Ward
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Ramtin
authors.initials: R
authors.lastname: Rahbar
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada; and.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
authors.affiliation: Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; jen.gommerman@utoronto.ca.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gommerman
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D018149:Glucose Intolerance / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology*; D053308:Lymphotoxin-beta / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000166:cytology / Q000276:immunology
chemical_list: D001324:Autoantigens; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; C505699:Ltbr protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D053259:Lymphotoxin beta Receptor; D053308:Lymphotoxin-beta