Engineering antigens for in situ erythrocyte binding induces T-cell deletion

Stephan Kontos, Iraklis C. Kourtis, Karen Y. Dane, Jeffrey A. Hubbell

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Antigens derived from apoptotic cell debris can drive clonal T-cell deletion or anergy, and antigens chemically coupled ex vivo to apoptotic cell surfaces have been shown correspondingly to induce tolerance on infusion. Reasoning that a large number of erythrocytes become apoptotic (eryptotic) and are cleared each day, we engineered two different antigen constructs to target the antigen to erythrocyte cell surfaces after i.v. injection, one using a conjugate with an erythrocyte-binding peptide and another using a fusion with an antibody fragment, both targeting the erythrocyte-specific cell surface marker glycophorin A. Here, we show that erythrocyte-binding antigen is collected much more efficiently than free antigen by splenic and hepatic immune cell populations and hepatocytes, and that it induces antigen-specific deletional responses in CD4+ and CD8+ T cells. We further validated T-cell deletion driven by erythrocyte-binding antigens using a transgenic islet β cell-reactive CD4+ T-cell adoptive transfer model of autoimmune type 1 diabetes: Treatment with the peptide antigen fused to an erythrocyte-binding antibody fragment completely prevented diabetes onset induced by the activated, autoreactive CD4+ T cells. Thus, we report a translatable modular biomolecular approach with which to engineer antigens for targeted binding to erythrocyte cell surfaces to induce antigen-specific CD4+ and CD8+ T-cell deletion toward exogenous antigens and autoantigens.

Original languageEnglish (US)
Pages (from-to)E60-E68
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number1
DOIs
StatePublished - Jan 2 2013

Keywords

  • Autoimmunity
  • BDC2.5
  • Immune tolerance
  • Immunoengineering
  • TER119

ASJC Scopus subject areas

  • General

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