Breaking tolerance with engineered class I antigen-presenting molecules

Christopher A. Parks, Kalli R. Henning, Kevin D. Pavelko, Michael J. Hansen, Virginia P. Van Keulen, Brendan K. Reed, Jennifer D. Stone, Adam G. Schrum, Diana Gil, David M. Kranz, Andrew J. Bordner, Michael A Barry, Larry R Pease

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Successful efforts to activate T cells capable of recognizing weak cancer-associated self-antigens have employed altered peptide antigens to activate T cell responses capable of cross-reacting on native tumor-associated self. A limitation of this approach is the requirement for detailed knowledge about the altered self-peptide ligands used in these vaccines. In the current study we considered allorecognition as an approach for activating CTL capable of recognizing weak or self-antigens in the context of self-MHC. Nonself antigen-presenting molecules typically contain polymorphisms that influence interactions with the bound peptide and TCR interface. Recognition of these nonself structures results in peptide-dependent alloimmunity. Alloreactive T cells target their inducing alloantigens as well as third-party alloantigens but generally fail to target self-antigens. Certain residues located on the alpha-1/2 domains of class I antigen-presenting molecules primarily interface with TCR. These residues are more conserved within and across species than are residues that determine peptide antigen binding properties. Class I variants designed with amino acid substitutions at key positions within the conserved helical structures are shown to provide strong activating signals to alloreactive CD8 T cells while avoiding changes in naturally bound peptide ligands. Importantly, CTL activated in this manner can break self-tolerance by reacting to self-peptides presented by native MHC. The ability to activate self-tolerant T cells capable of cross-reacting on self-peptide-MHC in vivo represents an approach for inducing autoimmunity, with possible application in cancer vaccines.

Original languageEnglish (US)
Pages (from-to)3136-3145
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number8
DOIs
StatePublished - Feb 19 2019

Keywords

  • Adenovirus
  • Cancer immunotherapy
  • MHC
  • T cells
  • Tolerance

ASJC Scopus subject areas

  • General

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    Parks, C. A., Henning, K. R., Pavelko, K. D., Hansen, M. J., Van Keulen, V. P., Reed, B. K., Stone, J. D., Schrum, A. G., Gil, D., Kranz, D. M., Bordner, A. J., Barry, M. A., & Pease, L. R. (2019). Breaking tolerance with engineered class I antigen-presenting molecules. Proceedings of the National Academy of Sciences of the United States of America, 116(8), 3136-3145. https://doi.org/10.1073/pnas.1807465116