RESUMO
Natural Killer (NK) cells are innate cytotoxic lymphocytes that possess features of adaptive immunity, including antigen specificity and clonal expansion. NK cells rapidly respond to cytokines released during the innate phase of viral infection and are thought to migrate from circulation into infected organs to execute their early effector functions. However, recent evidence suggests that tissue-resident NK cells are among the first responders to viral infection. In this study, we observe that antigen receptor signaling precedes substantial proinflammatory cytokine signaling in a population of NK cells during mouse cytomegalovirus infection. Early antigen receptor signals epigenetically prime NK cells for optimal expansion during the later adaptive phase of the antiviral response. Mechanistically, receptor signaling increases chromatin accessibility at STAT4-binding genomic sites within differentiating NK cells. To promote adaptive programming of NK cells during infection, activating receptor-dependent epigenetic remodeling antagonizes IL-12 driven terminal maturation, poises NK cells for proliferation via sustained CDK6 expression, and antagonizes early apoptosis of short-lived effector cells via suppression of Bim. Thus, antigen receptor signaling alters an IL-12 dependent fate decision during the innate-to-adaptive transition of antiviral NK cells.
RESUMO
BACKGROUND: Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component. METHODS AND RESULTS: In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 1,363 individuals with AAA compared to 27,260 age, ancestry, and sex-matched controls (1:20 case:control study design). A similar analysis was repeated for 435 individuals with TAA compared to 8,700 controls. Polymorphism with minor allele frequency (MAF) >0.5% were evaluated. We identified novel loci near LINC01021, ATOH8 and JAK2 genes that achieved genome-wide significance for AAA (p-value <5x10-8), in addition to three known loci. For TAA, three novel loci in CTNNA3, FRMD6 and MBP achieved genome-wide significance. There was no overlap in the genes associated with AAAs and TAAs. Additionally, we identified a linkage group of high-frequency variants (MAFs ~10%) encompassing FBN1, the causal gene for Marfan syndrome, which was associated with TAA. In FinnGen PheWeb, this FBN1 haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA. CONCLUSIONS: Our GWAS found that AAA and TAA were associated with distinct sets of genes, suggesting distinct underlying genetic architecture. We also found association between baseline bradycardia and TAA. These findings, including JAK2 association, offer plausible mechanistic and therapeutic insights. We also found a common FBN1 linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These FBN1 variants suggest shared pathophysiology between Marfan disease and sporadic TAA.