Editors' ChoiceLung Immunology

Better together: Alveolar macrophage and memory T cell cosignaling in ex vivo human lungs

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Science Translational Medicine  27 Jan 2021:
Vol. 13, Issue 578, eabg5637
DOI: 10.1126/scitranslmed.abg5637

Abstract

Ex vivo lung perfusion enables assessment of the resident adaptive immune system and provides insight into the lung response to pathogen exposure.

The lung’s constant exposure to the environment and its extensive vascularity with resultant high blood flow demand an effective and tightly regulated immune response. Inhaled and aspirated pathogens are an ever-present risk whereas an overexuberant reaction to non-pathologic antigens poses its own potential for injury and organ impairment. Murine models demonstrate that lungs contain significant populations of resident pathogen–specific CD4+ and CD8+ T cells that respond rapidly to repeated exposure to a given pathogen. In human lungs, recently identified tissue-resident memory T cells have been shown to be a key component of the local response to pathogens and act to decrease illness severity from recurrent infections. The precise mechanism of this effector response has yet to be determined. The complex relationship between systemic mediators of inflammation and tissue-specific factors makes unraveling the constituent elements a particular challenge using traditional intact model systems.

Snyder et al. detail an innovative approach in which they used an ex vivo perfusion (EVLP) model of the human lung to investigate interactions between lung resident macrophages and memory T cells and provide important insights into the foundations of the lung’s immune system. Using donor lungs declined for transplant, Snyder and colleagues infused anti-human CD45 antibody in the perfusate to label immune cells readily in contact with the circulation in order to differentiate them from immune cells resident within the parenchyma or airways, which they classified as protected cells. Subsequent analysis determined that these protected immune cells largely consisted of memory T cells with few naïve lymphocytes. Immunohistocytology analysis on lung biopsies found these resident memory T cells coclustered with tissue macrophages around airways where they are well-positioned to identify and respond to inhaled pathogens. To provide insight into functional effect of this coclustering, memory T cells were cocultured in the presence of tissue macrophages, which resulted in increased production of interferon-γ and tumor necrosis factor-α compared with control preparations. These results suggest an important role for tissue macrophages in stimulating activation of memory T cells.

Ex vivo lung perfusion is an important technique used clinically to assess marginal donor organs for use in lung transplantation. Snyder and colleagues now demonstrate that EVLP is also a powerful platform capable of investigating complex biological phenomena. Leveraging this modality further may provide critical insights into autoimmune disease, the antineoplastic role of the immune system, and how to condition transplant organs to reduce risk of acute and chronic rejection. Major hurdles limiting the efficacy of EVLP as an experimental platform include its technical complexity for reliable use and the short duration, on the order of hours, for which lungs can be maintained before degradation. The uncertain effects of ex vivo support on the core processes being studied are an additional challenge that have yet to determined. Despite these limitations, the emergence of EVLP as an experimental modality provides investigators with a vital tool in further understanding the complex immune system.

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