Induction of transporter associated with antigen processing by interferon γ confers endothelial cell cytoprotection against natural killer-mediated lysis

Oran Ayalon, Eric A. Hughes, Peter Cresswell, Jennifer Lee, Lynn O'Donnell, Ruggero Pardi, Jeffrey R. Bender

Research output: Contribution to journalArticlepeer-review

Abstract

T lymphocytes react minimally with nonactivated endothelial cells (ECs). However, natural killer (NK) lymphocyte interactions with resting ECs are rapid, avid, and result in endothelial activation and/or cytotoxicity. The molecular basis for these interactions and EC sensitivity to NK-mediated lysis is unclear. To address the EC-specific nature of NK sensitivity, we used syngeneic human umbilical vein ECs, dermal microvascular ECs, dermal fibroblasts, and B lymphoblastoid cell lines in calcein-AM retention NK assays with allogeneic NK effector cells and found the EC lines consistently more NK-sensitive. Because NK inhibitory receptors are engaged by membrane major histocompatibility complex (MHC) I molecules and MHC I-deficient targets are NK-sensitive, we investigated the quantitative levels of membrane MHC I on the panel of syngeneic lines. Highly sensitive ECs expressed similar (or higher) levels of membrane MHC I than their syngeneic NK-resistant counterparts. Pretreatment of ECs with γ Interferon (IFN-γ) conferred protection against NK-mediated lysis, with much more rapid kinetics (2-6 hr) than those required for membrane MHC I hyperinduction (>8 hr). These kinetics are consistent with induction of transporter associated with antigen processing (TAP) expression and function. As opposed to NK-resistant cell lines, TAP-1 was undetectable in resting ECs. Recombinant expression of the TAP inactivator ICP47 by adenoviral-mediated transduction was used to selectively inhibit IFN-γ-mediated EC TAP function. ICP47 expression abrogated EC cytoprotection conferred by IFN-γ. We demonstrate a relationship between both basal and induced TAP-1 expression/function and EC sensitivity to NK-mediated cytotoxicity. We discuss the influence of an induced MHC I-associated peptide repertoire on vascular vulnerability to cytotoxic lymphocytes.

Original languageEnglish
Pages (from-to)2435-2440
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number5
Publication statusPublished - Mar 3 1998

ASJC Scopus subject areas

  • General
  • Genetics

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