Deletion of naïve T cells recognizing the minor histocompatibility antigen HY with toxin-coupled peptide-MHC class I tetramers inhibits cognate CTL responses and alters immunodominance

Sabrina M. Hess, Ellen F. Young, Keith R. Miller, Benjamin G. Vincent, Adam S. Buntzman, Edward J. Collins, Jeffrey A. Frelinger, Paul R. Hess

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Alloreactive T-cell responses directed against minor histocompatibility (H) antigens, which arise from diverse genetic disparities between donor and recipient outside the MHC, are an important cause of rejection of MHC-matched grafts. Because clinically significant responses appear to be directed at only a few antigens, the selective deletion of naïve T cells recognizing donor-specific, immunodominant minor H antigens in recipients before transplantation may be a useful tolerogenic strategy. We have previously demonstrated that peptide-MHC class I tetramers coupled to a toxin can efficiently eliminate specific TCR-transgenic T cells in vivo. Here, using the minor histocompatibility antigen HY as a model, we investigated whether toxic tetramers could inhibit the subsequent priming of the two H2-Db-restricted, immunodominant T-cell responses by deleting precursor CTL. Immunization of female mice with male bone marrow elicited robust CTL activity against the Uty and Smcy epitopes, with Uty constituting the major response. As hypothesized, toxic tetramer administration prior to immunization increased survival of cognate peptide-pulsed cells in an in vivo CTL assay, and reduced the frequency of corresponding T cells. However, tetramer-mediated decreases in either T-cell population magnified CTL responses against the non-targeted epitope, suggesting that Db-Uty+ and Db-Smcy+ T cells compete for a limited common resource during priming. Toxic tetramers conceivably could be used in combination to dissect manipulate CD8+ T-cell immunodominance hierarchies, and to prevent the induction of donor-specific, minor H antigen CTL responses in allotransplantation.

Original languageEnglish (US)
Pages (from-to)138-145
Number of pages8
JournalTransplant Immunology
Volume29
Issue number1-4
DOIs
StatePublished - Dec 2013
Externally publishedYes

Keywords

  • Alloreactivity
  • Cytotoxic T lymphocytes
  • Immunodominance
  • MHC
  • Minor histocompatibility antigens
  • Tetramers

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Transplantation

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