Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function

J Immunol. 2010 Jan 15;184(2):598-606. doi: 10.4049/jimmunol.0900032. Epub 2009 Dec 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • Antigen-Presenting Cells / immunology*
  • Antigens / immunology*
  • Autoimmune Diseases / prevention & control
  • CD8-Positive T-Lymphocytes / immunology*
  • Histocompatibility Antigens Class II / genetics
  • Immunologic Memory*
  • Mice
  • Promoter Regions, Genetic

Substances

  • Antigens
  • Histocompatibility Antigens Class II