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

Publication ,  Journal Article
Getts, DR; Turley, DM; Smith, CE; Harp, CT; McCarthy, D; Feeney, EM; Getts, MT; Martin, AJ; Luo, X; Terry, RL; King, NJC; Miller, SD
Published in: J Immunol
September 1, 2011

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.

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Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

September 1, 2011

Volume

187

Issue

5

Start / End Page

2405 / 2417

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • Spleen
  • Peptides
  • Peptide Fragments
  • Myelin Proteolipid Protein
  • Mice, Inbred C57BL
  • Mice
  • Membrane Glycoproteins
  • Macrophages
  • Macrophage Activation
 

Citation

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Getts, D. R., Turley, D. M., Smith, C. E., Harp, C. T., McCarthy, D., Feeney, E. M., … Miller, S. D. (2011). Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. J Immunol, 187(5), 2405–2417. https://doi.org/10.4049/jimmunol.1004175
Getts, Daniel R., Danielle M. Turley, Cassandra E. Smith, Christopher T. Harp, Derrick McCarthy, Emma M. Feeney, Meghann Teague Getts, et al. “Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells.J Immunol 187, no. 5 (September 1, 2011): 2405–17. https://doi.org/10.4049/jimmunol.1004175.
Getts DR, Turley DM, Smith CE, Harp CT, McCarthy D, Feeney EM, et al. Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. J Immunol. 2011 Sep 1;187(5):2405–17.
Getts, Daniel R., et al. “Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells.J Immunol, vol. 187, no. 5, Sept. 2011, pp. 2405–17. Pubmed, doi:10.4049/jimmunol.1004175.
Getts DR, Turley DM, Smith CE, Harp CT, McCarthy D, Feeney EM, Getts MT, Martin AJ, Luo X, Terry RL, King NJC, Miller SD. Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. J Immunol. 2011 Sep 1;187(5):2405–2417.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

September 1, 2011

Volume

187

Issue

5

Start / End Page

2405 / 2417

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • Spleen
  • Peptides
  • Peptide Fragments
  • Myelin Proteolipid Protein
  • Mice, Inbred C57BL
  • Mice
  • Membrane Glycoproteins
  • Macrophages
  • Macrophage Activation