Circulating B7H6 is associated with reduced NKp30 receptor expression and improved lung transplant recipient survival

Lung transplantation prolongs survival for many patients with end-stage lung diseases, though long-term outcomes are limited due to allograft inflammation leading to chronic rejection. In this study, we aimed to identify the role of natural killer (NK) cell receptors in lung transplant recipient outcomes. We hypothesized that cystic fibrosis (CF) may be a model for systemic inflammation. Peripheral blood mononuclear cells were collected from recipients with CF (n = 6), recipients with chronic obstructive pulmonary disease (n = 6), and healthy donors (n = 7) for NK cell immunophenotyping via spectral flow cytometry and functional killing assays. Plasma B7H6 was also measured in 2 independent lung transplant cohorts to test the association with rejection. We identified a CF-specific reduction in NKp30 receptor expression, validated functionally against cells expressing the B7H6 ligand. The NKp30 reduction was not NK cell subset specific, suggesting a systemic influence. Further, we found that B7H6 in vitro reduced NKp30-mediated killing of target cells in a dose-dependent fashion. Analysis of soluble B7H6 concentrations in plasma revealed higher soluble B7H6 in CF recipients relative to other groups, suggesting a potentially broader role of soluble B7H6 in lung transplant outcomes. Consequently, B7H6 was higher in recipients without acute graft dysfunction, and higher B7H6 plasma concentrations conferred reduced risk of chronic lung allograft dysfunction (CLAD) and mortality. Single-cell RNA sequencing showed that B7H6 transcripts were most prevalent on ciliated airway epithelial cells and bronchoalveolar lavage monocytes and that airway B7H6 transcripts were reduced in CLAD. Thus, our data reveal a new role of the NKp30-B7H6 axis in potentiating lung allograft outcomes.