Cutting Edge: Pseudomonas aeruginosa Abolishes Established Lung Transplant Tolerance by Stimulating B7 Expression on Neutrophils

Abstract

The mechanisms that link bacterial infection to solid organ rejection remain unclear. Here we show that following the establishment of lung allograft acceptance in mice P. Aeruginosa (PA) airway infection induces a G-CSF-dependent neutrophilia that stimulates acute rejection. Graft-infiltrating neutrophils sharply upregulate the B7 molecules CD80 and CD86, but do not express CD40 or MHC Class II in response to PA infection. Neutrophil B7 promotes naïve CD4+ T cell activation and intragraft IL-2+, IFN-γ+ and IL-17+ T lymphocyte accumulation. Intravital 2-photon microscopy reveals direct interactions between neutrophils and CD4+ T cells within pulmonary allografts. Importantly, lung rejection in PA-infected recipients is triggered by CD80/86 on neutrophils and can be prevented by B7 blockade without affecting clearance of this pathogen. These data show that neutrophils enhance T cell activation through B7 trans-costimulation and suggest that inhibiting neutrophil-mediated alloimmunity can be accomplished without compromising bacterial immune surveillance.

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…Orthotopically transplanted mouse lungs are exposed to the environment, allowing for the design of experiments to evaluate the role of respiratory pathogens on alloimmunity and AR responses. Pseudomonas aeruginosa respiratory infections can break immunosuppression-mediated lung allograft tolerance (64). This model is a suitable platform to evaluate new diagnostic modalities for AR.…”

Update on lung transplantation: programmes, patients and prospects

“…Very recent studies have shown that P. aeruginosa can subvert tolerance in lung allografts by stimulating B7 expression on neutrophils [390]. This study points to the critical role that infection or colonisation may have on long-term outcomes.…”

“…P. aeruginosa, for example, has been shown to be capable of breaking allograft tolerance through the unusual paracellular mechanism of upregulating B7, a co-stimulation molecule usually found on dendritic cells and on neutrophils [390]. As Pseudomonas also has been shown to colonise damaged airways, both cause and effect possibilities exist for its presence in the airways being associated with a marked increased risk of BOS [239].…”

Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation

“…Neutrophil infiltration can also increase local inflammatory factors, including TNF-a and granulocyte colonystimulating factor (38). These processes can lead to further exposure of sequestered sAgs, causing propagation of lung-restricted autoimmunity (41,43).…”

“…In addition to macrophages, neutrophils also play a significant role in abrogating tolerance after administration of antibodies specific to lung sAgs. Neutrophil activation in the allograft leads to significant increase in CD4 1 T cell activation, as well as increase in IL-17, IFN-g, and IL-2 in the graft (41). Neutrophils are known to be an important source of IL-6 (42), and the matrix metalloproteinases secreted by neutrophils may influence tissue inflammation, leading to presentation of cryptic sAgs to the immune system.…”