Comparative Transcriptomic Analysis Reveals Shared Interferon-Associated Transcriptional Programs and...

Conventional dendritic cells (cDCs) are central regulators of antiviral immunity, translating Toll-like receptor signaling into coordinated gene expression programs. Human cDC subsets, including cDC1 and cDC2, exhibit distinct functional properties; however, the extent to which these subsets engage shared versus subset-associated transcriptional responses following Toll-like receptor 7 (TLR7) stimulation remains incompletely defined.

We performed an in silico transcriptomic re-analysis of publicly available NanoString gene expression data derived from purified human cDC1 and cDC2 populations. Analytical approaches included global expression profiling, principal component analysis, exploratory differential gene expression analysis, and module-based functional profiling of interferon, inflammatory, and antigen presentation pathways. Additional analyses included comparative fold-change assessment and integrated co-expression network analysis of immune-associated genes.

Global transcriptomic analysis demonstrated clear segregation of samples by stimulation status and dendritic cell subset, with consistent clustering of biological replicates. TLR7 activation induced substantial transcriptional remodeling in both subsets, with differences in the magnitude and distribution of regulated genes. Functional module analysis revealed stimulation-associated shifts in interferon-related and inflammatory transcriptional organization across both cDC1 and cDC2 cells, together with subset-associated variation in the relative magnitude and coordination of immune-associated transcriptional responses. Gene-level analysis further indicated strong induction of several canonical interferon-responsive genes, including ISG15, MX1, IFIT1, STAT1, and IRF7, in cDC2 cells, whereas cDC1 cells demonstrated comparatively more heterogeneous relative expression changes for several interferon-associated transcripts. Inflammatory mediators such as IL12B, TNF, CXCL10, and CCL3 likewise exhibited subset-associated variation in relative transcriptional responses. Integrated co-expression and hierarchical clustering analyses further suggested that TLR7-responsive immune genes form partially coordinated transcriptional networks rather than strictly isolated subset-specific pathways. In contrast, antigen presentation-related genes remained comparatively stable across conditions.

TLR7 stimulation is associated with partially shared interferon-associated transcriptional organization across human cDC subsets, accompanied by subset-associated variation in inflammatory and immune transcriptional responses, highlighting overlapping but non-identical innate immune activation architectures across dendritic cell subsets.