Interferon-gamma receptor-Janus kinase signaling pathway (IFNGR-JAK pathway)

The Interferon-gamma (IFN-γ) receptor-Janus kinase (JAK) signaling pathway is a fundamental immunological axis that mediates the cellular response to type II interferon. Signaling is initiated when IFN-γ binds to its heterotetrameric receptor complex, composed of IFNGR1 and IFNGR2 subunits, which triggers the activation of the associated kinases JAK1 and JAK2 (UniProt P15260, P01579). These kinases then phosphorylate STAT1, which forms homodimers and translocates to the nucleus to drive the transcription of genes involved in antiviral defense, MHC expression, and pro-inflammatory signaling (PubMed 28410989). In the tumor microenvironment, this pathway is responsible for bystander effects, where IFN-γ secreted by activated T-cells can induce changes in neighboring cells, such as the upregulation of PD-L1 and MHC molecules, which can lead to adaptive immune resistance or enhanced antigen presentation (PubMed 32029621). Therapeutic targeting of this pathway is employed in various conditions: JAK inhibitors like ruxolitinib are used to treat myeloproliferative neoplasms and inflammatory diseases, while the monoclonal antibody emapalumab is used to neutralize excess IFN-γ in patients with primary hemophagocytic lymphohistiocytosis (FDA Label: Gamifant, Jakafi).

Other names

IFN-gamma signaling pathwayIFNGR-JAK-STAT pathwayType II interferon signaling pathwayIFN-gamma receptor-JAK signaling pathway

Inhibition of Janus kinases (JAK1/JAK2) to prevent STAT1 phosphorylation and downstream gene transcription; neutralization of the IFN-gamma ligand to prevent receptor binding and activation.