title: Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function.
abstract: Memory T cells develop early during the preclinical stages of autoimmune diseases and have traditionally been considered resistant to tolerance induction. As such, they may represent a potent barrier to the successful immunotherapy of established autoimmune diseases. It was recently shown that memory CD8+ T cell responses are terminated when Ag is genetically targeted to steady-state dendritic cells. However, under these conditions, inactivation of memory CD8+ T cells is slow, allowing transiently expanded memory CD8+ T cells to exert tissue-destructive effector function. In this study, we compared different Ag-targeting strategies and show, using an MHC class II promoter to drive Ag expression in a diverse range of APCs, that CD8+ memory T cells can be rapidly inactivated by MHC class II+ hematopoietic APCs through a mechanism that involves a rapid and sustained downregulation of TCR, in which the effector response of CD8+ memory cells is rapidly truncated and Ag-expressing target tissue destruction is prevented. Our data provide the first demonstration that genetically targeting Ag to a broad range of MHC class II+ APC types is a highly efficient way to terminate memory CD8+ T cell responses to prevent tissue-destructive effector function and potentially established autoimmune diseases.
authors.affiliation: Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Brisbane, Australia.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Kenna
authors.forename: Tanya
authors.initials: T
authors.lastname: Waldie
authors.forename: Alice
authors.initials: A
authors.lastname: McNally
authors.forename: Meagan
authors.initials: M
authors.lastname: Thomson
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000941:Antigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000517:prevention & control; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D007156:Immunologic Memory; D051379:Mice; D011401:Promoter Regions, Genetic
chemical_list: D000941:Antigens; D000949:Histocompatibility Antigens Class II