{
  "abstract": "Introduction Systemic sclerosis associated interstitial lung disease (SSc-ILD) is a major cause of morbidity and leading cause of death among SSc patients. Natural killer (NK) cells are increasingly implicated in immune dysregulation and fibrosis, but most studies have focused on blood, with conflicting results. The role of lung-resident NK cells remains largely unexplored.Material and Methods Lung tissues from 13 SSc-ILD and 6 healthy controls along with peripheral blood from 27 SSc and 6 controls were analyzed using 3’ 10X scRNA-seq. After normalization and batch-correction, NK cell subpopulations were identified without integration to preserve tissue-specific signatures. Differential expression analysis, and module scoring (Seurat AddModuleScore), and curated exhaustion gene set were used to quantify functional NK cell states. To interrogate intercellular communication, CellChat and DeCoupleR were applied to infer pathway-level interactions, focusing on pro-fibrotic and inflammatory cascades.Results We identified a distinct NK cell subpopulation in SSc-ILD characterized by concurrent activation and exhaustion. These NK cells highly expressed IFNG, GZMB, and amphiregulin (AREG), consistent with cytotoxic and pro-remodeling activity, while also showing increased levels of TIGIT, LAG3, HAVCR2, PDCD1, BATF2, and ENTPD1. Pathway enrichment analysis revealed selective enrichment of inflammatory and pro-fibrotic signaling cascades (NFkB, TNF-a, TGF-B, MAPK) unique to lung SSc-ILD NK cells ( figure 1). Exhaustion module scores were markedly elevated in lung nk cells from ssc-ild, with >65% of cells scoring high for exhaustion markers, compared to ~40-55% in blood and control lungs (figure 2). This divergence highlights the dominance of the lung microenvironment in shaping NK cell dysfunction.Conclusions Lung NK cells in SSc-ILD exhibit a paradoxical phenotype of heightened cytotoxic activation coupled with profound exhaustion, distinct from blood NK cells. These findings identify a lung-specific NK cell program as a mechanistic driver of disease and highlight NK cell exhaustion as a potential therapeutic target, supporting strategies aimed at restoring NK cell function to alter disease progression.Abstract P.048 Figure 1–2",
  "authors": [
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, USA"
      ],
      "name": "Cristina Padilla"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, USA"
      ],
      "name": "John Sembrat"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, USA"
      ],
      "name": "Tracy Tabib"
    },
    {
      "affiliations": [
        "University of Pittsburgh, Pittsburgh, USA"
      ],
      "name": "Robert Lafyatis"
    }
  ],
  "title": "P.048 Lung NK cells in SSC-ILD exhibit a paradoxical activated-exhausted state",
  "uid": "95654f76-226d-5d5e-8cf2-4a0137a993cd"
}