Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells

Daniel R. Getts, Danielle M. Turley, Cassandra E. Smith, Christopher T. Harp, Derrick McCarthy, Emma M. Feeney, Meghann Teague Getts, Aaron J. Martin, Xunrong Luo, Rachael L. Terry, Nicholas J C King, Stephen D. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

129 Scopus citations


Ag-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide Ags linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-coupled splenocytes [Ag-SP]) has been demonstrated to be a highly efficient method for inducing peripheral, Ag-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy. In this study, we show that apoptotic Ag-SP accumulate in the splenic marginal zone, where their uptake by F4/80+ macrophages induces production of IL-10, which upregulates the expression of the immunomodulatory costimulatory molecule PD-L1 that is essential for Ag-SP tolerance induction. Ag-SP infusion also induces T regulatory cells that are dispensable for tolerance induction but required for long-term tolerance maintenance. Collectively, these results indicate that Ag-SP tolerance recapitulates how tolerance is normally maintained in the hematopoietic compartment and highlight the interplay between the innate and adaptive immune systems in the induction of Ag-SP tolerance. To our knowledge, we show for the first time that tolerance results from the synergistic effects of two distinct mechanisms, PD-L1-dependent T cell-intrinsic unresponsiveness and the activation of T regulatory cells. These findings are particularly relevant as this tolerance protocol is currently being tested in a Phase I/IIa clinical trial in new-onset relapsing-remitting multiple sclerosis.

Original languageEnglish (US)
Pages (from-to)2405-2417
Number of pages13
JournalJournal of Immunology
Issue number5
StatePublished - Sep 1 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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