Tissue-resident NK Cell Metabolism and Function in the Human Lung — ASN Events
  1. Schedule
  2. Poster Session One
  3. Tissue-resident NK Cell Metabolism and Function in the Human Lung

Tissue-resident NK Cell Metabolism and Function in the Human Lung (#143)

Gráinne Jameson 1 , Aaron Walsh 1 , Robbie Woods 1 , Isabella Batten 1 , Dearbhla Murphy 1 , Sarah A Connolly 1 , Oisin O’Gallchobhair 1 , Parthiban Nadarajan 2 , Finbarr O’Connell 2 , Laura Gleeson 1 2 , Joseph Keane 1 2 , Sharee Basdeo 1
  1. Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
  2. Respiratory, St James Hospital, Dublin 8, Ireland

Background:
Tissue-resident NK (trNK) cells, defined as CD49a+CD56brightCD16-NK cells, are enriched in the human lung and demonstrate heightened responsiveness to infection compared to non-trNK cells (CD49a-CD56brightNK cells). Emerging evidence indicates that trNK cells may become dysfunctional in disease states. Given the tractability of NK cells for therapeutic immunomodulation, targeting their metabolism to support functionality represents a promising strategy.

Aims and Methods:
This study aimed to evaluate whether trNK cells possess a distinct metabolic profile compared to circulating NK cells. Flow cytometry and SCENITH were used to assess residency marker expression and metabolic profiles in bronchoalveolar lavage (BAL)- and blood-derived NK subsets (n=5-14). An in vitro lung model was optimized using BAL-conditioned medium to induce a tissue-resident phenotype in circulating NK cells (n=7). Functional responses of NK cells were analysed upon bacterial and cytokine stimulation.

Results:
Lung trNK cells exhibit a unique metabolic signature characterized by higher glycolytic capacity, glucose dependence, and higher expression of effector function-associated genes compared to non-trNK cells in both lung and blood. Non-trNK cells in the lung show an intermediate metabolic profile, suggesting adaptation towards a tissue-resident phenotype. In the in vitro lung model, circulating NK cells cultured with BAL-conditioned medium adopted a trNK-like phenotype and metabolic profile (induced-trNK). These induced-trNK cells displayed significantly reduced IFNγ and TNFα responses to stimulation, likely reflecting the microenvironment's influence on NK cell functionality.

Conclusion:
Lung trNK cells have a distinctive metabolic profile that supports their effector functions during infection. The reduced functional responses of induced-trNK cells in the in vitro model underscore the critical role of the lung microenvironment in shaping NK cell activity. Optimized models are essential to study NK cell behaviour and responses within tissue-specific microenvironments, with implications for developing metabolic-targeted immunotherapies.