<h3>Purpose</h3> Quilty Lesions (QL) are enigmatic polytypic inflammatory cellular aggregates seen in some heart transplant biopsies. The study was designed to investigate genetic pathways that might be activated in heart transplant biopsies with QL. <h3>Methods</h3> Nine heart allograft biopsies from one institution were included in the study. Tissue was stained for H/E and biopsies separated as having QL (5) vs. no QL (4). Total RNA was then extracted from FFPE. RNA extraction and gene analysis was performed using the Nanostring n-Counter Human Organ Transplant Immunology Panel (Seattle, WA). <h3>Results</h3> The heat map (Figure 1) shows a clear separation between biopsies with QL and biopsies without QL. Pathways that were upregulated in biopsies with QL included: NK-kappa Beta, cytokine signaling, chemokine signaling, cytotoxicity, type II interferon, Toll-like receptor, B-cell receptor, T-cell checkpoint, lymphocyte trafficking, oxidative stress, MAPK, Class II Ag presentation, complement system, Class I antigen presentation, TNF family, NLR family, cell cycle regulation, mTOR, inflammasomes, TGF-beta, epigenetics and transcription, T-reg differentiation, Th1 differentiation, Th2 differentiation, Th17 differentiation, cytosolic DNS sensing, innate immune system, adaptive immune system, hematopoiesis, T-cell receptor signaling, cell-ECM interaction. In contrast, the following pathways were downregulated in biopsies with QL: autophagy, angiogenesis, tissue homeostasis. Biopsies with QL showed a predominance of adaptive type Th2 response over Th1genes (3.88x vs. 3.15x). Individual regulatory genes (all p< 0.001) that were higher in biopsies with QL included TGFbeta1, IL10RA, Foxp3 and JAK3. <h3>Conclusion</h3> Heart allograft biopsies with QL showed a clearly differential expression of genes compared to biopsies without QL. Pathways and individual upregulated genes suggest a shift towards regulation and acceptance of the allograft. QL, far from being passive bystanders, may have a positive immunomodulatory function in cardiac allografts.