Dendritic cells (DCs) are immune sentinels that bridge innate and adaptive immunity by recognising, processing and presenting antigens to T cells through major histocompatibility complex (MHC). DCs are also major producers of type I and type III interferons (IFNs), such as IFN-α/β and IFN-λ respectively, and are among the few haematopoietic cells that express the IFN-λ receptor (IFN-λR). Comparatively, the IFN-α receptor (IFNAR) is ubiquitously expressed. As major producers of type I and III IFNs and having high receptor expression, DCs and their function are therefore likely to be greatly influenced by IFNs. The current dogma suggests that type I and III IFNs share redundant functions due to a high degree of similarity shared in known post-receptor signalling events. However, the majority of this research has been conducted in epithelial cells and limited research exists validating this in DCs.
Using RNA sequencing, ATAC sequencing, phosphoproteomics, and total proteomics, we identified distinct patterns of gene and protein regulation in DCs following IFN-α and IFN-λ stimulation. IFN-α induced robust changes in transcriptome regulation and chromatin accessibility, whereas IFN-λ-mediated responses were greatly limited. In contrast, both IFNs strongly modulated protein expression to a comparable extent, including differential regulation of phosphoproteins and total proteins. These findings indicate that IFN-λ primarily shapes DC responses through post-translational modifications, while IFN-α exerts combined effects on the transcriptome and proteome.
Integrated analysis of proteomics, ATAC sequencing and RNA sequencing datasets, revealed a potential modulation of the transforming growth factor (TGF)-β signalling pathway specifically in IFN-λ–treated DCs. TGF-β signalling is critical for cellular processes such as proliferation, differentiation, and apoptosis, and plays an immunosuppressive role in maintaining homeostasis. The observed regulation of TGF-β signalling in response to IFN-λ suggests a context-dependent, dichotomous role for IFN-λ in immune modulation, where it may act as both as a stimulator and suppressor of immune responses.
IFNs are required for an effective immune response, however, we currently have limited knowledge of IFN-mediated signalling pathways in DCs. My findings aim to uncover precise signalling dynamics and define unique functions induced by IFN-α and IFN-λ in DCs. It is imperative to elucidate these functions, as understanding IFN-mediated responses in DCs could inform strategies to better harness DCs in immunotherapies to treat a range of diseases, including cancer.