Natural killer cells in lung transplantation

Abstract

Natural killer (NK) cells are innate lymphoid cells that have been increasingly recognised as important in lung allograft tolerance and immune defence. These cells evolved to recognise alterations in self through a diverse set of germline-encoded activating and inhibitory receptors and display a broad range of effector functions that play important roles in responding to infections, malignancies and allogeneic tissue. Here, we review NK cells, their diverse receptors and the mechanisms through which NK cells are postulated to mediate important lung transplant clinical outcomes. NK cells can promote tolerance, such as through the depletion of donor antigen-presenting cells. Alternatively, these cells can drive rejection through cytotoxic effects on allograft tissue recognised as ‘non-self’ or ‘stressed’, via killer cell immunoglobulin-like receptor (KIR) or NKG2D receptor ligation, respectively. NK cells likely mediate complement-independent antibody-mediated rejection of allografts though CD16A Fc receptor-dependent activation induced by graft-specific antibodies. Finally, NK cells play an important role in response to infections, particularly by mediating cytomegalovirus infection through the CD94/NKG2C receptor. Despite these sometimes-conflicting effects on allograft function, enumeration of NK cells may have an important role in diagnosing allograft dysfunction. While the effects of immunosuppression agents on NK cells may currently be largely unintentional, further understanding of NK cell biology in lung allograft recipients may allow these cells to serve as biomarkers of graft injury and as therapeutic targets.

Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury

“…Our findings may have broader implications, as NK cells can play multiple important roles in the context of lung transplantation (45). In addition to the effects observed on IRI, NK cells appear to impact CLAD outcomes both through immune surveillance of CMV (46) and depletion of host antigen-presenting cells (47).…”

Telomere Dysfunction Drives Chronic Lung Allograft Dysfunction Pathology

“…We speculate that senescence reprogramming due to telomere dysfunction in club cells leads to release of an array of cytokines and chemokines that attract immune cells to the lung. Elevated numbers of T cells and NK cells could reflect a direct response to cell stress (37) or be due to T-cell attracting chemokines released by senescent club cells, such as CXCL-9, CXCL-10 and CXCL-11, that are commonly elevated in airway inflammation (38) and CLAD (39,40). Elevated levels of lymphocytes in lungs of SCGB1a1-cre TRF1 F/F transgenic mice suggests that telomere dysfunction in club cells could even contribute to the inflammatory changes seen in CLAD.…”

Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance

“…When the lung alveolar surfaces are exposed to pathogens and harmful materials, the innate immune system, including NK cells, provides initial protection [ 152 , 153 , 154 , 155 , 156 ]. In humans, NK cells accounting for about 10–20% of the lymphocytes in the lungs [ 107 ] In mice, 10% of lymphocytes consist of NK cells [ 107 , 157 ].…”