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

The Interferon-gamma (IFN-gamma) receptor-Janus kinase (JAK) signaling pathway is a central coordinator of cell-mediated immunity and pro-inflammatory responses [1]. The pathway is initiated when a homodimer of IFN-gamma binds to the extracellular domains of the IFN-gamma receptor complex, which consists of two IFNGR1 (alpha) subunits and two IFNGR2 (beta) subunits [2]. This binding triggers the activation of receptor-associated Janus kinases, specifically JAK1 and JAK2, which then phosphorylate the intracellular tail of the receptor to create docking sites for STAT1 [3]. Phosphorylated STAT1 homodimerizes and translocates to the nucleus to bind Gamma-Activated Sequences (GAS) in the promoters of target genes, such as those encoding MHC molecules, chemokines (e.g., CXCL9, CXCL10), and antiviral proteins [4]. A critical feature of this pathway is its bystander activity; because IFN-gamma is a secreted soluble factor, it can activate the JAK-STAT pathway in neighboring immune and non-immune cells that are not the primary targets of the producing T cells or NK cells, thereby shaping the broader tissue microenvironment [5]. While essential for host defense, overactivation of this pathway is a hallmark of cytokine storm syndromes like hemophagocytic lymphohistiocytosis (HLH) and can contribute to autoimmune pathology [6]. Conversely, in oncology, the pathway is involved in both anti-tumor responses and the induction of adaptive resistance mechanisms, such as the upregulation of PD-L1 on tumor and bystander cells [7]. Therapeutic modulation includes the use of the neutralizing antibody emapalumab for HLH and various JAK inhibitors for inflammatory and myeloproliferative conditions [8].

Other names

IFN-gamma signaling pathwayIFNGR1/IFNGR2-JAK1/JAK2 complexType II interferon signalingIFN-gamma-JAK-STAT1 axisIFN-gamma receptor-Janus kinase signaling pathway on target and bystander immune cells

Inhibition of IFN-gamma ligand binding to its receptor or inhibition of the downstream Janus kinase (JAK1/JAK2) enzymatic activity to prevent STAT1-mediated gene transcription.