A Novel Long Noncoding RNA MSTRG.479558.1 Regulates Immune Response in Dendritic Cells

Dendritic cells (DCs) are central orchestrators of adaptive immunity, integrating innate immune sensing with antigen-specific T-cell activation. While long noncoding RNAs (lncRNAs) have emerged as critical regulators of immune cell fate and function, the lncRNA landscape governing human DC differentiation and effector activity remains incompletely defined. Here, we generated monocyte-derived dendritic cells (moDCs) from primary human peripheral blood monocytes and performed transcriptome-wide RNA sequencing to systematically identify previously unannotated lncRNAs associated with DC differentiation. We uncovered an extensive repertoire of novel lncRNA transcripts dynamically regulated during DC development. Among these, MSTRG.479558.1 and MSTRG.582898.5 were prioritized based on robust induction during differentiation, responsiveness to inflammatory stimulation (LPS), and elevated expression in periodontitis. Functional interrogation revealed a selective and non-redundant role for MSTRG.479558.1 in DC biology. Knockdown of the lncRNA MSTRG.479558.1 but not MSTRG.582898.5 significantly reduced the expression of dendritic cell markers CD1a, CD209, and CDw93, indicating impaired dendritic cell differentiation. Functionally, MSTRG.479558.1 silencing profoundly impaired phagocytic capacity and antigen processing, indicating disruption at the earliest stages of antigen handling. Moreover, loss of MSTRG.479558.1 compromised antigen presentation and significantly attenuated DC-mediated CD4⁺ T-cell activation, and Th1 related cytokines IFNγ and TNF-α, suggesting a functional link between this lncRNA and adaptive immune priming. Mechanistically, targeted transcriptional profiling demonstrated coordinated dysregulation of genes implicated in antigen processing and presentation pathways following MSTRG.479558.1 depletion, including components of proteasomal processing, chaperone-mediated folding, and MHC-associated peptide loading machinery. These findings support a model in which MSTRG.479558.1 acts as an upstream regulator of a transcriptional network that governs antigen handling and presentation. Collectively, this study defines a previously uncharacterized lncRNA program operative during human DC differentiation and identifies MSTRG.479558.1 as a critical regulator of DC functional competency. By coupling antigen acquisition to T-cell activation, this lncRNA represents a novel layer of immune regulation with potential implications for inflammatory disease pathogenesis and therapeutic targeting.