Pseudomonas aeruginosa toxin reduces MHC class I antigen presentation

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen critical to the pathogenesis of nosocomial infections, chronic obstructive pulmonary disease (COPD), ventilator‐associated pneumonia (VAP) and Cystic Fibrosis (CF). Cif, a bacterial toxin secreted by laboratory and clinical isolates of P. aeruginosa, inhibits the intracellular trafficking of a variety of ABC transporters. Cif accesses epithelial cells via the lipid raft machinery and traffics retrograde to the ER. In the current study, we tested the hypothesis that Cif regulates the transporter associated with antigen processing (TAP), thereby regulating antigen presentation by MHC class I. Cif reduced TAP1 abundance and MHC class I plasma membrane expression in a time‐ and concentration‐dependent manner in polarized human airway epithelial cells, concurrent with an increase in Cif‐mediated ubiquitination of these proteins. Proteosome inhibitors prevented Cif‐induced degradation of TAP1 and MHC class I molecules. Furthermore, Cif decreased MHC class I presentation of peptide in a time‐dependent manner in a T‐cell tumor line. These observations predict that Cif, by promoting the degradation of TAP1 and reducing the presentation of peptide‐loaded MHC class I to the plasma membrane, will reduce the ability of cytotoxic T lymphocytes to eliminate viral/bacterial infections, severely compromising the immune defenses of the lung in patients with CF, COPD and VAP.